Methods and Systems for Optimizing Perivascular Neuromodulation Therapy Using Computational Fluid Dynamics

ABSTRACT

Methods and systems for optimizing perivascular neuromodulation therapy using computational fluid dynamics. Digital data regarding three-dimensional imaging of a target blood vessel and corresponding hemodynamic data are inputs to generating a computational fluid dynamics (CFD) model. The CFD model enables identification of one or more regions of the vessel suitable for neuromodulation therapy and/or identifying one or more regions of the vessel to avoid during such therapy. A system of the present technology can include a neuromodulation catheter, a computing device that can generate and analyze the CFD model, and a user interface for displaying the vessel with indicia for target regions and/or avoidance regions.

TECHNICAL FIELD

The present technology is related to perivascular neuromodulation. Inparticular, various embodiments of the present technology are related tomethods and systems for informed decision-making regarding whether todeliver neuromodulation therapy to various regions of a target bloodvessel.

BACKGROUND

The sympathetic nervous system (SNS) is a primarily involuntary bodilycontrol system typically associated with stress responses. Fibers of theSNS extend through tissue in almost every organ system of the human bodyand can affect characteristics such as pupil diameter, gut motility, andurinary output. Such regulation can have adaptive utility in maintaininghomeostasis or in preparing the body for rapid response to environmentalfactors. Chronic activation of the SNS, however, is a common maladaptiveresponse that can drive the progression of many disease states.Excessive activation of the renal SNS in particular has been identifiedexperimentally and in humans as a likely contributor to the complexpathophysiology of hypertension, states of volume overload (e.g., heartfailure), and progressive renal disease.

Sympathetic nerves of the kidneys terminate in the renal blood vessels,the juxtaglomerular apparatus, and the renal tubules, among otherstructures. Stimulation of the renal sympathetic nerves can cause, forexample, increased renin release, increased sodium reabsorption, andreduced renal blood flow. These and other neural-regulated components ofrenal function are considerably stimulated in disease statescharacterized by heightened sympathetic tone. For example, reduced renalblood flow and glomerular filtration rate as a result of renalsympathetic efferent stimulation is likely a cornerstone of the loss ofrenal function in cardio-renal syndrome, (i.e., renal dysfunction as aprogressive complication of chronic heart failure). Pharmacologicstrategies to thwart the consequences of renal sympathetic stimulationinclude centrally-acting sympatholytic drugs, beta blockers (e.g., toreduce renin release), angiotensin-converting enzyme inhibitors andreceptor blockers (e.g., to block the action of angiotensin II andaldosterone activation consequent to renin release), and diuretics(e.g., to counter the renal sympathetic mediated sodium and waterretention). These pharmacologic strategies, however, have significantlimitations including limited efficacy, compliance issues, side effects,and others.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present technology can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present technology. For ease of reference,throughout this disclosure identical reference numbers may be used toidentify identical or at least generally similar or analogous componentsor features.

FIG. 1 is a block diagram illustrating a method of evaluating a bloodvessel for neuromodulation therapy based on a computational fluiddynamics (CFD) model in accordance with an embodiment of the presenttechnology.

FIG. 2 is a partially schematic illustration of a neuromodulation systemconfigured in accordance with an embodiment of the present technology.

FIG. 3 is a side view of a distal portion of the neuromodulationcatheter of FIG. 2 positioned within a blood vessel.

FIG. 4 is a graphical representation of a computational fluid dynamicsmodel of a blood vessel in accordance with an embodiment of the presenttechnology.

FIG. 5 is a partially schematic illustration of a neuromodulation systemconfigured in accordance with another embodiment of the presenttechnology.

FIG. 6 is a side view of the distal portions of the neuromodulationcatheter and the sensing guidewire of FIG. 5 positioned within a bloodvessel.

FIGS. 7-9 are anatomic and conceptual side views, cross-sectional views,and enlarged views of a blood vessel illustrating a plurality ofphysiologic and pathologic features.

FIG. 10 illustrates modulating renal nerves with a neuromodulationcatheter described herein in accordance with an additional embodiment ofthe present technology.

FIG. 11 is a block diagram illustrating an overview of devices on whichsome implementations of the present technology may operate.

FIG. 12 is a block diagram illustrating an overview of an environment inwhich some implementations of the present technology may operate.

FIG. 13 is a conceptual illustration of the sympathetic nervous system(SNS) and how the brain communicates with the body via the SNS.

FIG. 14 is an enlarged anatomic view of nerves innervating a left kidneyto form the renal plexus surrounding the left renal artery.

FIGS. 15 and 16 are anatomic and conceptual views, respectively, of ahuman body depicting neural efferent and afferent communication betweenthe brain and kidneys.

FIGS. 17 and 18 are anatomic views of the arterial vasculature andvenous vasculature, respectively, of a human.

DETAILED DESCRIPTION

Methods and systems in accordance with embodiments of the presenttechnology can be configured to detect hemodynamic parameters of apatient's blood vessel, generate one or more models of the vessel, andanalyze region(s) of the vessel to inform decision-making regardingpotential regions for delivering neuromodulation therapy. Regions of thevessel may be identified for delivering therapy (e.g., target regions)while other regions may be identified as unsuitable for the therapy(e.g., avoidance regions). Specific details of several embodiments ofthe present technology are described herein with reference to FIGS.1-18. Although many of the embodiments are described with respect todevices, systems, and methods for catheter-based perivascular renalneuromodulation, other applications and other embodiments in addition tothose described herein are within the scope of the present technology.For example, at least some embodiments of the present technology may beuseful for intraluminal neuromodulation, extravascular neuromodulation,non-renal neuromodulation, and/or use in therapies other thanneuromodulation.

It should be noted that other embodiments in addition to those disclosedherein are within the scope of the present technology. Further,embodiments of the present technology can have different configurations,components, and/or procedures than those shown or described herein.Moreover, a person of ordinary skill in the art will understand thatembodiments of the present technology can have configurations,components, and/or procedures in addition to those shown or describedherein and that these and other embodiments can be without several ofthe configurations, components, and/or procedures shown or describedherein without deviating from the present technology.

As used herein, the terms “distal” and “proximal” define a position ordirection with respect to a clinician or a clinician's control device(e.g., a handle of a neuromodulation catheter). The terms, “distal” and“distally” refer to a position distant from or in a direction away froma clinician or a clinician's control device along the length of device.The terms “proximal” and “proximally” refer to a position near or in adirection toward a clinician or a clinician's control device along thelength of device. The headings provided herein are for convenience onlyand should not be construed as limiting the subject matter disclosed.

I. Selected Embodiments of Systems for Evaluating a Vessel forNeuromodulation Therapy and Associated Methods

Renal perivascular neuromodulation therapy aims to modulate theautonomic nervous system, specifically the SNS, by modulating ordestroying renal efferent sympathetic nerves and afferent renal sensorynerves. However, delivering neuromodulation therapy in a vessel at alocation having a local flow abnormality and/or a region of secondaryflow increases a risk that a patient could experience an unwanted eventin response to therapy. Local flow abnormalities and/or regions ofsecondary flow are not visible with conventional methods of vascularimaging, such as fluoroscopy. Therefore, the patient can benefit frommethods and systems configured to display or otherwise inform a user(e.g., a clinician) of locations in the target blood vessel having localflow abnormalities and/or regions of secondary flow. In this way, theclinician can reduce the risk of an unwanted event by avoidingdelivering neuromodulation therapy at these locations. The presenttechnology includes several embodiments of methods and systems foravoiding delivering neuromodulation therapy to locations in the vesselhaving local flow abnormalities and/or regions of secondary flow. Thesemethods and systems are configured to provide visual, audible, and/ortactile feedback to guide positioning of a neuromodulation catheter 210at one or more suitable therapeutic locations in the patient's vessel.

FIG. 1 is a block diagram illustrating a method 100 of evaluating ablood vessel for delivery of neuromodulation therapy based on acomputational fluid dynamics (CFD) model in accordance with anembodiment of the present technology. As shown in FIG. 1, the method 100includes receiving digital three-dimensional imaging data regarding ablood vessel at a processor (block 110). The three-dimensional imagingdata of the vessel can represent a renal artery, a pulmonary artery, ahepatic artery, a coronary artery, an aorta, and/or other blood vesselssuitable for neuromodulation therapy. In some embodiments, the vesselcan be a main vessel (e.g., renal artery), at least one branch vessel ofthe main vessel (e.g., posterior or anterior branch of the renalartery), at least one accessory vessel directly coupled to the branchvessel (e.g., inferior anterior segmental artery or interior segmentalartery) or another vessel coupled to the main vessel (e.g., aorta),and/or a combination thereof. The digital three-dimensional imaging datacan be generated, in part, using input from one or more of the followingmodalities: angiography (e.g., x-ray, single-view, multi-view, computedtomography, positron emission, single positron emission), ultrasound,digital x-ray (e.g., contrast), digital fluoroscopy, magnetic resonanceimaging (MRI) (e.g., contrast or non-contrast), computed tomography (CT)(e.g., spiral, helical, dual source), and/or a modality otherwisesuitable for generating three-dimensional imaging input in a digitalformat. The three-dimensional imaging data can include information aboutone or more features of the blood vessel. For example, the informationcan include data corresponding to at least one dimension of a feature ofthe vessel, such as a cross-sectional area, a cross-sectional diameter,a volume, a length, and/or a combination thereof. In other embodiments,the feature can be a vessel wall or portion thereof (e.g., adventitia,media, and intima), a lumen, a branch, a bifurcation, a carina, anostium, a taper region, an aneurysm, fibromuscular dysplasia, anocclusion, an impingement, a calcification, an intimal deposit, and/or acombination thereof. These features are described in detail below withreference to FIGS. 7-9.

In addition to receiving the three-dimensional imaging data at theprocessor, the method 100 includes receiving hemodynamic data regardingthe blood vessel sensors (block 120). For example, the receivedhemodynamic data can be measurement of blood pressure, blood flow, bloodimpedance, viscosity of the patient's blood, other hemodynamicparameters, and/or combinations thereof. The received hemodynamic datacan be based on measurements taken inside the vessel, outside thevessel, outside the patient's body, and/or a combination thereof. Bloodviscosity can be assumed or measured. For example, blood viscosity isassumed to be 3×10⁻³ to 4×10⁻³ pascal-seconds (e.g., similar to water).

The blood pressure data, blood flow data, blood impedance data, and/or acombination thereof can be measured by one or more sensors, such as asensor coupled to a neuromodulation catheter positioned in the targetblood vessel in accordance with the present technology. In someembodiments, the method 100 includes coupling a sensor to the patient todetect and record data corresponding to one or more hemodynamicparameters either before or during an intravascular treatment. Thesensor can be an external device that is coupled to the patient, forexample, positioned near the patient's vessel. For example, the sensorcan be an external pressure cuff, a Doppler ultrasound flow meter, amagnetic resonance imaging (MRI) machine, and/or combinations thereof.The sensor can alternatively be an internal device positioned within thepatient, such as delivered transluminally into the patient's vessel. Forexample, the sensor can be coupled to a neuromodulation catheter 210that can be delivered transluminally into the vessel. The transluminallydelivered neuromodulation catheter can be positioned within a portion ofthe patient's vessel having laminar flow, and/or otherwise positioned toperform measurements of one or more hemodynamic parameters. The sensorcan include, for example, a blood flow sensor, a blood pressure sensor,a blood impedance sensor, and/or a combination thereof. For example, thesensor can be a combination blood pressure-blood flow sensor carried bya guidewire (e.g., the blood pressure and blood flow sensor(s) can bethe same sensor or different sensors located on the same guidewire) suchas a fractional flow reserve (FFR) guidewire. In some embodiments, thecombination guidewire also includes a transducer. In some embodiments,the method 100 can include coupling more than one sensor to the patient.

Several embodiments of the method 100 include measuring blood flow,blood pressure, and/or blood impedance in a main portion of the vessel(e.g., renal artery) and/or a branch of the main artery (e.g., anteriorand/or posterior branch of renal artery). The measurements can beperformed in a portion of the main vessel, or branch thereof, havingstable (e.g., laminar) flow, a portion having unstable (e.g., turbulent,varied, secondary) flow, and/or a combination thereof.

After receiving the hemodynamic data, the method 100 continues bygenerating a computational fluid dynamics (CFD) model or representationof the target vessel based at least in part on the three-dimensionalimaging data of the vessel (block 110) and the hemodynamic data (block120). Using equations, algorithms, and various statistical methods,information regarding the three-dimensional imaging data of the vessel(e.g., vessel geometry) and hemodynamic data (e.g., blood pressure,blood flow, blood impedance, and/or blood viscosity) can be used togenerate the CFD model of the vessel. The CFD model can be generatedusing a CFD workflow or other suitable methods for generating the CFDrepresentation. The CFD workflow begins by fabricating a volumetric meshto align with certain features of the vessel (e.g., geometry)represented by the three-dimensional imaging data. The hemodynamic data(e.g., blood flow data and/or blood pressure data) can be used to formone or more boundary conditions of the CFD simulation (e.g., the inlet)in the CFD workflow. The CFD workflow can generate a flow field and, ifmore than one CFD model is generated (e.g., different CFD models can begenerated for certain portion of the vessel), the CFD models can becoupled (e.g., at the outlets) such that blood flow/blood pressurerelationships can be computed. In some embodiments, the blood pressuredata can be a proximal boundary condition and each outlet (e.g., distalboundary) can be coupled to a zero-dimensional representation of bloodimpedance, resistance, and compliance/capacitance of the patient'scirculation distal to the boundaries. The CFD model can be displayedusing one resolution in an image or multiple resolutions in a singlerepresentation. For example, a first portion of the CFD model can have alower resolution compared to a second portion. Use of the lowerresolution in the first portion is expected to reduce duration ofcertain computing parameters such that the CFD model having at least tworesolutions can be generated faster than a CFD model having theresolution of the second portion displayed across the CFD model. In someembodiments, the CFD model can be validated using suitable validationmethodologies (e.g., invasively measured values).

The user (e.g., clinician) and/or a computer can form certainassumptions about one or more features of the vessel physiology andhemodynamics or other information input into the CFD model. For example,an assumption can be that blood behaves as an incompressible fluidand/or a region of the vessel (e.g., segmented region) has rigid walls.In some embodiments, one or more hemodynamic parameters can be derivedfrom empirical data, conglomerate data, and/or a combination thereof. Inthese embodiments, the CFD model of the vessel can be generated, inpart, by applying one or more hemodynamic parameters derived fromempirical data or conglomerate data to the CFD workflow. Empirical datacan be obtained from a population database generated by the user oranother party. The population database can include blood pressure dataand/or blood flow data, each of which can be generalized. For example,generalized blood pressure can be 120/80 mmHg and generalized blood flowcan be 500 ml/min. In additional embodiments, the CFD representation caninclude sample waveforms (e.g., measured, calculated, or standard) usingcomputational methods such as ensemble averaging.

The CFD model is expected to aid in characterization and display ofconventionally difficult to measure physiological and pathologicalparameters throughout the vessel targeted for perivascular denervation.CFD models are expected to quickly and accurately provide informationregarding the vessel using anatomically accurate geometry andhemodynamically accurate inputs of the vessel. Iterative processing ofCFD models can achieve convergence regarding physiological andpathological aspects of the modeled vessel(s). Measuring vessel wallshear stress (“WSS”) is difficult and invasive without CFD models whichcan map spatial distribution of WSS, one of several physiologicalfeatures that may be desirable to avoid when delivering neuromodulationtherapy.

Based on the CFD model generated by the processor (block 130), themethod 100 can continue by identifying, with the processor, targetregions and/or avoidance regions of the vessel for deliveringneuromodulation therapy (block 140). Locations of avoidance regions canbe identified on the CFD model by the processor using equations,algorithms, various statistical methods, and/or analysis of thepatient's anatomical features, by user observation, and/or by acombination thereof. The avoidance regions can be one or more regions ofthe vessel having a local flow abnormality, a physiologic feature,and/or a pathologic feature (e.g., diseases) (collectively “flowabnormality”). In some embodiments, flow abnormalities are associatedwith an increased risk of an unwanted event following neuromodulationtherapy. Local flow abnormalities can include, but are not limited to, aregion of secondary flow (e.g., turbulent flow, flow separation, andeddy formation), flow impingement, low WSS, high WSS, and/or WSSgradients. Avoidance regions can include one or more pathologic featuresof vascular disease (e.g., a calcification, a fibromuscular dysplasia,an aneurysm) and/or one or more physiologic features of the vessel(e.g., an ostium, a carina, a taper region, a bifurcation) and/or acombination thereof. In other embodiments (not shown), the method 100can include identifying, via the processor, target regions of the vesselsuitable for neuromodulation therapy The target regions, for example,can be one or more regions of the vessel lacking a local flowabnormality, a physiologic feature, and/or a pathologic featureassociated with an increased risk of an unwanted event followingneuromodulation therapy.

The target regions can be identified by determining if measured valuesof the hemodynamic parameters at a given location are within “normal”ranges or above/below values of the hemodynamic parameters indicative ofno local flow abnormalities and/or no regions of secondary flow (e.g.,threshold hemodynamic parameters). For example, if the hemodynamicparameter is blood pressure, then a blood pressure value within the“normal” range for blood pressure at the given location could trigger arecommendation to deliver neuromodulation therapy at the given location(e.g., a target region). Similarly, the avoidance regions can beidentified by determining if measured values of the hemodynamicparameters at the given location are outside “normal” ranges orbelow/above the values of the hemodynamic parameters indicative of localflow abnormalities and/or regions of secondary flow. For example, ablood pressure value outside of the “normal” range for blood pressure atthe given location could trigger a recommendation to avoid deliveringneuromodulation therapy at the given location (e.g., an avoidanceregion). Each corresponding threshold hemodynamic parameter can bedetermined using empirical, conglomerate, or other suitable data usefulto establish the threshold hemodynamic parameter. For example, thresholdhemodynamic parameters can be determined for blood flow, blood pressure,blood impedance, and/or other hemodynamic parameters measured using themethods described herein.

The method 100 may use an algorithm executed by the processor to compareone or more hemodynamic parameters against one or more thresholdhemodynamic parameters. The threshold hemodynamic parameter can bepredetermined or can be calculated before performing the comparison. Insome embodiments, the processor that analyzes the hemodynamic parameterscan include algorithms that remove any apparent irregular hemodynamicparameter(s) to automatically correct for the anomalies. In otherembodiments, the comparison between the one or more hemodynamicparameters and one or more threshold hemodynamic parameters can be madeby users, systems, devices, and/or a combination thereof. In furtherembodiments, the algorithm can use two or more hemodynamic parametersand/or other data to provide a combined hemodynamic parameter that ismore closely tied to identifying target and/or avoidance regions of thevessel than any one individual hemodynamic parameter alone.

The method 100 optionally continues by displaying a representation ofthe vessel including visual markers indicating one or more avoidanceregions for not delivering neuromodulation therapy on a user interface(block 150). Also see FIG. 4 and corresponding description below. Insome embodiments (not shown), the displayed representation can alsoinclude markers of one or more target regions of the vessel fordelivering neuromodulation therapy. In other embodiments, therepresentation can have more than one portion of the vessel displayed,such as a first portion and a second portion. The first portion and thesecond portion can be contiguous or separated (e.g., a different portionseparates the first portion from the second portion). The displayedfirst portion can correspond to one or more regions suitable fordelivering neuromodulation therapy (e.g., target regions), whereas thedisplayed second portion can correspond to one or more avoidance regionsto avoid delivering neuromodulation therapy. Different features of therepresentation can be displayed using different resolutions. Each of theavoidance regions and the target regions can be visually displayed onthe representation using unique corresponding indicia such as colors,shading, patterns, shapes, and/or combinations thereof. For example, theavoidance regions could be displayed on the representation using a red,round shape (e.g., a red circle) encompassing the avoidance regionswhereas target regions could be displayed using a green, round shape(e.g., a green circle) around the target regions. Similarly, avoidanceregions could be displayed using a shape having a red color gradientwith a center of the avoidance regions colored a dark red and the sidescolored in a pale red. Target regions could be similarly displayed withgreen gradient colored shapes. In some embodiments, potential vesseltreatment having no data or inconclusive data could be encompassed witha yellow round shape (e.g., yellow circle) having a solid color or agradient of color. In other embodiments, different colors, patterns, andshapes (e.g., arrows) could be displayed to indicate avoidance regions,target regions, and potential regions. The CFD model information thusprovided to the clinician can be used to optimize the neuromodulationprocedure.

With reference to the vessel evaluation results displayed on the userinterface, the clinician can deliver neuromodulation catheter 210 to thepatient's vessel while monitoring the location of the catheter withinthe vessel. As described in greater detail below with reference to FIG.10, the neuromodulation catheter can be delivered to the patient'svessel using the methods described herein in accordance with the presenttechnology or, alternatively, using other methods suitable fordelivering the catheter. For example, the location of a portion of theneuromodulation catheter (e.g., neuromodulation assembly 230) can bemonitored while the catheter is being positioned within the vessel. Insome embodiments, the location can be monitored by visually observingassembly 230 during delivery to the vessel. Alternatively, dataregarding the current location (e.g., monitored location) of assembly230 in the vessel can be sent to the processor, e.g. by a signal emittedby a transmitter incorporated in or otherwise coupled to theneuromodulation catheter. The user can receive the feedback signal viauser interface and/or another signal emitting device configured to emitthe visual, audio, and/or tactile signal in accordance with embodimentsof the present technology. In certain embodiments, the location of theneuromodulation assembly can be monitored in real-time.

In further embodiments, after receiving the catheter location data, theprocessor can provide a recommendation to the user of whether to proceedwith neuromodulation therapy based on whether the current location ofassembly 230 includes an identified avoidance region and/or targetregion. The recommendation can include recommending the user avoiddelivering neuromodulation therapy to the one or more identified regionsof the patient's vessel (e.g., an avoidance region) or recommending theuser deliver neuromodulation therapy to the one or more identifiedregions (e.g., a target region). In some embodiments, the recommendationcan be provided while delivering and/or positioning the neuromodulationcatheter. In other embodiments, the recommendation can be providedbefore or after delivering and/or positioning the catheter.

In some embodiments, the recommendation can be provided to the user viathe user interface, for example, by displaying the recommendation on adisplay or emitting a signal. The signal can be a visual signal, anaudio signal, a tactile signal, or a combination thereof. For example,the visual signal can be emitted by a device (e.g., a light) that turnson when assembly 230 is positioned proximate to the one or moreidentified regions. For example, the recommendation can be a light thatturns green when assembly 230 is positioned proximate to or within anidentified target region and/or a light that turns red when positionedproximate to or within an identified avoidance region. In otherembodiments, the device can be a speaker, a vibration mechanism, orother device suitable for conveying the signal to the user. In additionto the display and/or signal, the recommendation can be provided to theuser by exhibiting one or more of the hemodynamic parameters and/or anoverall hemodynamic parameter on a visual display or other deviceconfigured to receive the hemodynamic parameter(s) and provide therecommendation. In further embodiments, the three-dimensionalrepresentation, CFD model, and/or other representation can be stored toguide positioning of the neuromodulation catheter at a later time,and/or computations performed after the image and/or representationswere obtained and/or generated. In these embodiments, the image and/orrepresentations can be stored, analyzed, and/or computations performedusing a component of the device and/or environment. Furthermore, theprocessor can also provide a report that distributes the hemodynamicparameters to the user on a smart phone, a computer, a tablet computer,and/or other device including a digital display.

A method of the present technology can include applying neuromodulationenergy to at least one of the target regions using a neuromodulationcatheter 210. In other embodiments, the target region(s) can be markedas locations for future neuromodulation therapy. When one or more of thehemodynamic parameter(s) are elevated above a corresponding thresholdhemodynamic parameter(s) at a location, the location can be identifiedas an avoidance region. If neuromodulation energy were to be deliveredat an identified avoidance region, there is a concern that the patientcould have sequelae, such as swelling, edema, stenosis, a tear, rupture,dilation, dissection, and/or thrombus, associated with deliveringneuromodulation therapy at that location.

In further embodiments, the method and systems described herein can beused to monitor the vessel following neuromodulation therapy todetermine if an unwanted event has occurred or might occur. Changes inblood flow and/or blood pressure following neuromodulation therapy canindicate that an unwanted event might occur at one or more of theregions, or at another region of the vessel. If an unwanted event doesoccur, the user can opt to treat the patient accordingly.

II. Selected Embodiments of Neuromodulation Systems

FIG. 2 is a partially schematic illustration of a neuromodulation system200 (“system 200”) in accordance with an embodiment of the presenttechnology. The system 200 can be used in conjunction with method 100described above with references to FIG. 1 to assess one or morehemodynamic parameters and/or identify one or more avoidance regionsand/or target regions for delivering neuromodulation therapy. Inaddition, the system 200 and embodiments thereof can be used to deliverneuromodulation therapy to the patient.

As shown in FIG. 2, the system 200 includes a neuromodulation catheter210, a console 295, and a cable 275 operatively coupling theneuromodulation catheter 210 to the console 295. The neuromodulationcatheter 210 includes an elongated shaft 220 having a proximal portion220 a and a distal portion 220 b, a handle 270 operably connected to theshaft 220 at the proximal portion 220 a, and a neuromodulation assembly230 at the distal portion 220 b of the shaft 220. The distal portion 220b of the shaft 220 is configured to be moved within a lumen of thepatient and locate the neuromodulation assembly 230 at a target regionwithin the lumen. For example, the shaft 220 can be configured toposition the neuromodulation assembly 230 within a blood vessel, a duct,an airway, or another naturally occurring lumen within the human body.

The shaft 220 and the neuromodulation assembly 230 can be 2, 3, 4, 5, 7,or 8 French size or another suitable size. The dimensions (e.g., outerdiameter and length) of the distal portion 220 b of the shaft 220 can beselected to accommodate the vessels or other body lumens in which thedistal portion 220 b of the neuromodulation catheter 210 is designed tobe delivered. For example, the axial length of the distal portion 220 b,may be selected to be no longer than a patient's renal artery (e.g.,typically less than 8 cm), and have a deployed or expanded diameter thataccommodates the inner diameter of a typical renal artery and/or thebranches of the renal artery (e.g., about 2-10 mm, e.g., about 4-8 mm,for the renal artery RA, etc.). In addition, the neuromodulationassembly 230 can include a shape memory portion having shape memorymaterial, such as nickel-titanium alloy, that imparts a helical orspiral shape to the neuromodulation assembly 230 when expanded. In otherembodiments, the shaped portion of the neuromodulation assembly 230 canhave other dimensions depending on the body lumen within which it isconfigured to be deployed.

As illustrated, the neuromodulation assembly 230 includes a sensor 240,a transmitter 245, and a plurality of energy delivery elements 260 a-g(collectively energy delivery elements 260). In this embodiment, thesensor 240 is disposed at the distal end (e.g., terminal tip) of thedistal portion 220 b and the transmitter 245 is disposed proximal to theenergy delivery elements 260. In other embodiments, the sensor 240and/or the transmitter 245 can be disposed at different locationssuitable for the sensor 240 to detect one or more hemodynamic parametersand/or for the transmitter 245 to transmit the location of theneuromodulation assembly 230 to a receiver 287 in accordance withembodiments described herein. For example, the sensor 240 can beproximal to and/or the transmitter 245 can be distal to one or moreenergy delivery elements 260. The sensor 240 and the transmitter 245 canbe connected to one or more supply wires (not shown) that convey energyto the sensor 240 and transmitter 245. Alternatively, the sensor 240and/or the transmitter 245 can be coupled operatively to the console 295by dedicated wires and/or wirelessly (e.g., Bluetooth, radio wave,etc.). In embodiments where neither the sensor 240 nor the transmitter245 is located at the catheter distal end, the neuromodulation assembly230 can have an atraumatic tip (not shown). In certain embodiments, theneuromodulation assembly 230 can include more than one sensor 240 and/ortransmitter 245. The sensor 240, the transmitter 245 and theneuromodulation assembly 230 can be integrated into a singleneuromodulation catheter 210 as illustrated, or one or more of thesensors 240 and/or the transmitters 245 can be provided separately fromthe neuromodulation catheter 210, as will be discussed below.

The sensor 240 can detect a physiological parameter, such as ahemodynamic parameter, and the transmitter 245 can communicate to thereceiver 287 a signal related to the location of the neuromodulationassembly 230 in the vessel. The sensor 240 can include one or moresensors, for example, a blood velocity sensor (e.g., a Doppler laservelocity sensor or an ultrasonic flow meter) that can detect blood flowthrough a vessel (e.g., renal artery RA), a pressure sensor thatmeasures the blood pressure within the vessel, a blood impedance sensor(e.g., single or multi-electrode) that can determine changes in vesseldiameter, and/or other suitable sensors for detecting one or morehemodynamic parameters. As will be appreciated by those skilled in theart, blood is more conductive than vessel tissue and, therefore, vesselimpedance, i.e. blood impedance is lower when the vessel has a largerdiameter (i.e., when more blood is contained in the vessel) and higherwhen the vessel has a smaller diameter (i.e., when less blood iscontained in the vessel). Accordingly, when the sensor 240 is a singleor multi-electrode impedance sensor, blood impedance measurements takenby the sensor 240 can be correlated to changes in vessel diameter,segmental volume, and/or cross-sectional area (i.e., a hemodynamicresponse). In some embodiments, the blood impedance measurements can beused to assess the efficacy of the neuromodulation treatment. Similar tovessel diameter, blood flow and blood pressure are expected to change inresponse to a stimulus, and these changes are expected to occur to alesser degree after neuromodulation than before neuromodulation.Therefore, the changes in blood flow and/or vessel pressure measurementscaused by an electrical or pharmacological stimulus can be detectedbefore and after neuromodulation and then compared to threshold valuesto determine the efficacy of neuromodulation therapy. Furtherembodiments of monitoring hemodynamic responses to stimuli are disclosedin PCT Patent Application Number PCT/US15/534999, filed Oct. 1, 2015,entitled “Systems and Methods for Evaluating Neuromodulation Therapy viaHemodynamic Responses”, which is incorporated by reference herein in itsentirety.

In some embodiments, the sensor 240 can detect more than one hemodynamicparameter in the vessel. For example, the sensor 240 can include asensor configured to detect blood flow and blood pressure in the renalartery. In other embodiments, the sensor 240 can include different oradditional sensors that detect and/or record other information such asone or more of temperature (e.g., thermocouple, thermistor, etc.),optical, chemical, and/or other parameters. The sensor 240 sensor(s) canfurther be configured to record data associated with the detectedhemodynamic parameters. In some embodiments, the recordings can be madeby another component of the system 200.

The transmitter 245 can include one or more sensors, for example, afirst sensor, a second sensor, a third sensor, a fourth sensor, etc.configured to monitor the location of the neuromodulation assembly 230in the vessel. In some embodiments, each sensor of the transmitter 245can be configured to monitor the location of specific energy deliveryelements 260 (e.g., electrodes). For example, the first sensor can beconfigured to monitor a location of energy delivery elements 260 a and260 b, the second sensor can be configured to monitor the location ofenergy delivery elements 260 c and 260 d, the third sensor can beconfigured to monitor the location of energy delivery elements 260 e and260 f, and the fourth sensor can be configured to monitor the locationof energy delivery element 260 g. In other embodiments, each sensor canhave a certain range and can monitor the location of any portion of theneuromodulation assembly 230, or the location of the transmitterrelative to any features of the vessel (e.g., wall, ostium, bifurcation,etc.) located within the range. The sensor(s) of the transmitter 245 canfurther be configured to record data associated with the monitoredlocation. In some embodiments, the location recordings can be made byanother component of the system 200.

In other embodiments, the neuromodulation assembly 230 can have fewer ormore than seven energy delivery elements 260. As illustrated in FIG. 2,the neuromodulation assembly 230 includes seven energy delivery elements260 a-g. The energy delivery elements 260 can be configured to applyelectrical stimuli (e.g., RF energy) to identified target regions at orproximate to one or more vessels within the patient, to temporarily stunnerves, and/or to deliver neuromodulation energy to target regions. Theenergy delivery elements 260 can be connected to one or more supplywires (not shown) that convey energy to the energy delivery elements260. In some embodiments, the energy delivery elements 260 areelectrodes. In various embodiments, certain energy delivery elements 260can be dedicated to applying stimuli, and other energy delivery elements260 can be other types of therapeutic elements, such as transducers orother elements, to deliver energy to modulate perivascular nerves usingother suitable neuromodulation modalities, such as pulsed electricalenergy, microwave energy, optical energy, ultrasound energy (e.g.,intravascularly delivered ultrasound, extracorporeal ultrasound, and/orhigh-intensity focused ultrasound (HIFU)), direct heat energy, radiation(e.g., infrared, visible, and/or gamma radiation), and/or other suitabletypes of energy. In certain embodiments, the neuromodulation catheter210 may be configured for cryotherapeutic treatment, and can applycryogenic cooling to the renal artery RA with a refrigerant (e.g., via aballoon catheter that circulates the refrigerant). In this embodiment,the system 200 can include a refrigerant reservoir (not shown) coupledto the neuromodulation catheter 210, and can be configured to supply theneuromodulation catheter 210 with refrigerant. In still otherembodiments, the neuromodulation catheter 210 is configured forchemical-based treatment (e.g., drug infusion), and the neuromodulationcatheter 210 can dispense intraluminally or inject transluminally one ormore chemicals to the treatment region to effectuate neuromodulation.Such chemicals can include neurotoxins (e.g., ethanol), adrenergicantagonists (e.g., guanethidine), and/or tissue necrosis-inducing agents(e.g., ethyl alcohol). In this embodiment, the system 200 can include achemical reservoir (not shown) and can be configured to supply theneuromodulation catheter 210 with one or more chemicals. In certainembodiments, one or more sensors and/or sensors may be located proximateto, within, or integral with the energy delivery elements 260.

The energy delivery elements 260 (e.g., electrodes) can be positioned onthe neuromodulation assembly 230 in one or multiple planes in a varietyof patterns. In the illustrated embodiment, the energy delivery elements260 are positioned on the shape memory portion of the neuromodulationassembly 230 such that many or all of the energy delivery elements 260press against or otherwise contact the interior vessel wall (e.g., renalartery RA wall). In other embodiments, multiple energy delivery elements260 can be positioned in the same plane orthogonal to the renal arteryRA to deliver stimuli and/or obtain multiple recordings in the sameplane of the interior vessel wall. When in contact with the interiorvessel wall, the energy delivery elements 260 and/or another type ofenergy delivery element can deliver neuromodulation energy to the targetregion to modulate or ablate nerves proximate to the target region. Itis expected that a successful or effective neuromodulation treatment ortherapy (i.e., when nerves are ablated to a desired degree) stops orattenuates nerve activity.

Although the illustrated embodiment of the neuromodulation assembly 230is configured with the spiral/helix-shape, in other embodiments, thedistal portion 220 b of the shaft 220 can have other suitable shapes(e.g., semi-circular, curved, straight, etc.), and/or theneuromodulation catheter 210 can include multiple support membersconfigured to carry one or more energy delivery elements 260 and pressthe energy delivery elements 260 against the interior vessel wall. Othersuitable devices and technologies are described in, for example, U.S.patent application Ser. No. 12/910,631, filed Oct. 22, 2010; U.S. patentapplication Ser. No. 13/279,205, filed Oct. 21, 2011; U.S. patentapplication Ser. No. 13/279,330, filed Oct. 23, 2011; U.S. patentapplication Ser. No. 13/281,360, filed Oct. 25, 2011; U.S. patentapplication Ser. No. 13/281,361, filed Oct. 25, 2011; PCT ApplicationNo. PCT/US11/57754, filed Oct. 25, 2011; U.S. Provisional PatentApplication No. 71/646,218, filed May 5, 2012; U.S. patent applicationSer. No. 13/793,647, filed Mar. 11, 2013; U.S. Provisional PatentApplication No. 71/961,874, filed Oct. 24, 2013; and U.S. patentapplication Ser. No. 13/670,452, filed Nov. 7, 2012. All of theforegoing applications are incorporated herein by reference in theirentireties. Non-limiting examples of devices and systems include theSymplicity™ RF ablation catheter and the Symplicity Spyral™multielectrode RF ablation catheter.

The console 295 of system 200 can be configured to control, monitor,supply, and/or otherwise support operation of the neuromodulationcatheter 210 and the CFD modeling of FIG. 1. As illustrated in FIG. 2,the console 295 includes a controller 280, a processor 285, the receiver287, and a user interface 297. For example, the CFD models generated bymethod 100 and embodiments thereof can be displayed as one or moreimages 298 on the user interface 297. In other embodiments, rather thanhaving the user interface 297 integrated with the console 295, the userinterface can be a separate component, such as a monitor (not shown),that displays the image 298. In certain embodiments, the console 295 canhave more than one user interface 297, or the system 200 can have both aseparate monitor (not shown) and the user interface 297 integrated withthe console 295. The console 295 can be configured to generate aselected form and/or magnitude of energy for delivery to tissue at thetarget region via the neuromodulation assembly 230, and therefore, theconsole 295 may have different configurations depending on the treatmentmodality of the neuromodulation catheter 210. For example, when theneuromodulation catheter 210 is configured for electrode-based,heat-element-based, or transducer-based treatment, the console 295 caninclude an energy generator (not shown) configured to generate RF energy(e.g., monopolar and/or bipolar RF energy), pulsed electrical energy,microwave energy, optical energy, ultrasound energy (e.g.,intravascularly delivered ultrasound, extracorporeal ultrasound, and/orHIFU), direct heat energy, radiation (e.g., infrared, visible, and/orgamma radiation), and/or another suitable type of energy.

In selected embodiments, the console 295 and neuromodulation catheter210 may be configured to deliver a monopolar electric field via one ormore of the energy delivery elements 260. In such embodiments, a neutralor dispersive energy delivery element (not shown) may be electricallyconnected to the console 295 and attached to the exterior of thepatient. In embodiments including multiple energy delivery elements 260,the energy delivery elements 260 may deliver power independently in amonopolar fashion, either simultaneously, selectively, or sequentially,and/or may deliver power between any desired combinations of the energydelivery elements 260 in a bipolar fashion. In addition, a user maymanually select which energy delivery elements 260 are activated forpower delivery in order to form highly customized lesion(s) within thelumen (e.g., renal artery), as desired.

The controller 280 and processor 285 can define a computing device thatincludes memory and is configured to receive and store imaging data,hemodynamic data (e.g., measured values of a hemodynamic parameterdetected by the sensor 240) and/or the location data (e.g., magneticsignals transmitted by the transmitter 245). The memory can beconfigured to store instructions that, when executed by the computingdevice, cause the system 200 to perform certain operations in accordancewith the present technology, such as executing embodiments of blocks110, 120, 130, 140 and 150 of method 100 described above with respect toFIG. 1.

In addition to avoiding delivering neuromodulation energy at one or moreavoidance regions as described above, additional embodiments of methodsand systems of the present technology can determine efficacy and/or riskto optimize a neuromodulation procedure. For example, the sensor 240 canbe positioned proximal to the treatment region to detect or measure oneor more hemodynamic parameter(s) after applying neuromodulatory energy.In addition, the transmitter 245 can be positioned near (e.g., proximalor distal) to the treatment region to convey information to the userabout the location of the neuromodulation assembly 230 in the vessel.The controller 280 can include algorithms that generate a comparison ofthe patient's pre-neuromodulation and post-neuromodulation information(e.g., hemodynamic parameters, imaging data, etc.). Since one or morehemodynamic parameters can change in response to energy delivery, thecomparison can provide the user with an indication of whetherneuromodulation therapy was effective, and/or whether there is risk of,or an actual unwanted event. In certain embodiments, the comparison canbe referenced against a standardized or patient-specific thresholdchange or level indicative of therapeutically effective neuromodulationand/or a risk of an unwanted event. The comparison can be provided tothe user via the user interface 297 or other component (e.g., amonitor). Based on the comparison, the user can determine whether theneuromodulation therapy achieved the desired effect, or if the therapyaffected hemodynamic parameter(s) and/or a structural feature of thevessel (e.g., wall thickness, rupture, intimal delamination, etc.). Ifthe comparison indicates that neuromodulation therapy was not effectiveand/or that the risk of experiencing an unwanted event has increased,subsequent monitoring and/or subsequent courses of treatment can beperformed. For example, the neuromodulation assembly 230 can berepositioned along the vessel (e.g., renal artery RA) and/or rotated tomodulate nerves at a different position or in a different plane.

FIG. 3 is a side view of the neuromodulation assembly 230 of FIG. 2positioned within a renal blood vessel in accordance with anotherembodiment of the present technology. In other embodiments, theneuromodulation catheter 210 may be positioned in other vessels fordelivering neuromodulation therapy at different regions within the humanpatient. As illustrated, the system 200 includes a guide catheter 320configured to locate the distal portion 220 b of the neuromodulationcatheter 210 intravascularly at a treatment region within the bloodvessel (e.g., the renal artery RA). In operation, intraluminal deliveryof the neuromodulation assembly 230 can include percutaneously insertinga guidewire (not shown) into a body lumen of a patient and moving theshaft 220 (FIG. 2) and/or the neuromodulation assembly 230 along theguidewire until the neuromodulation assembly 230 reaches a target region(e.g., a renal artery). For example, a distal end of the neuromodulationassembly 230 may define a passageway for engaging the guidewire fordelivery of the neuromodulation assembly 230 using over-the-wire (OTW)or rapid exchange (RX) techniques. In other embodiments, theneuromodulation catheter 210 can be a steerable or non-steerable deviceconfigured for use without a guidewire. In still other embodiments, theneuromodulation catheter 210 can be configured for delivery via a sheath(not shown).

During a procedure, the neuromodulation assembly 230 extends distally ofthe distal portion 330 of the guide catheter 320 and into the vessellumen. As the neuromodulation assembly 230 is advanced through thevessel lumen, for example, the sensor 240 senses laminar blood flowthrough a proximal portion of the lumen. When the neuromodulationassembly encounters potential avoidance regions such as a stenosis 351,and/or a bifurcation 315, the sensor 240 detects a change in thepreviously laminar blood flow. The sensor 240 transmits the blood flowdata to the receiver 287 and, as described above, other components ofthe system 200 generate the CFD model based, in part, on the blood flowdata. As described above, the system 200 identifies and recommendsavoidance regions and target regions for delivering neuromodulationenergy.

Once positioned in the target blood vessel, the neuromodulation assembly230 is transformed from a low-profile delivery state (not shown) fordelivery (e.g., intravascularly through the aorta) to a deployed state(e.g., radially expanded state). When deployed, the energy deliveryelements 260 are pressed against the inner wall of the vessel andneuromodulation energy can be selectively delivered to the identifiedtarget regions. After delivering neuromodulation energy, the system 200is configured to sense post-neuromodulation therapy parameters anddetermine the efficacy and/or the risk of an unwanted event as describedabove. If necessary, the user can reposition the neuromodulationassembly 230 to deliver additional neuromodulation therapy at one ormore different identified target locations. To reposition theneuromodulation assembly 230, the user can return the assembly 230 tothe low-profile delivery state and re-deploy the neuromodulationassembly 230 at a new location. In some embodiments, the location of theneuromodulation assembly 230 during positioning, deployment,repositioning, re-deployment, and/or a combination thereof can bedisplayed on the user interface 297 in real-time.

FIG. 4 illustrates a representation (“representation 400”) of a bloodvessel in accordance with an embodiment of the present technology. Therepresentation 400 is a CFD image 407 displaying visual indicatorscorresponding to target regions 440, potential regions 450, andavoidance regions 460 determined in accordance with embodiments ofblocks 110, 120, 130 and 140 of the method 100. The CFD image 407depicts a vessel 405 including a proximal portion 430 a and a distalportion 430 b with a main portion of the vessel 405 extending therebetween. The CFD image 407 further depicts a right branch 410 and a leftbranch 420 extending from the vessel 405 at a bifurcation 415 into theright portion 430 d and the left portion 430 c, respectively. In theillustrated embodiment, avoidance regions 460 are indicated by densehash marks, target regions 440 are indicated by sparse hash marks, andpotential regions 450 are illustrated by moderate hash marks. In otherembodiments, the avoidance regions 460, potential regions 450, andtarget regions 440 can be individually indicated by a color, a shade ofthe color, more than one color, more than one shade of the color, one ormore patterns, shapes, and/or combinations thereof. For example,avoidance regions 460 could be indicated by a red marker, potentialregions 450 by a yellow marker, and target regions 440 by a greenmarker, with each marker enclosing the boundaries of the correspondingregion.

In some embodiments, the neuromodulation assembly 230 (not shown) can bepositioned in the vessel 405 while the user is viewing therepresentation 400. Referring in part to FIGS. 2 and 3, for example,representation 400 can guide positioning of the neuromodulation assembly230 in the vessel when the user can visually determine where theneuromodulation assembly 230 is positioned with respect to an avoidanceregion 460, a potential region 450, or a target region 440. Accordingly,the clinician can refer to the representation 400 and select orde-select particular energy delivery elements 260 to avoid deliveringneuromodulation therapy to the patient at identified and displayedavoidance regions 460 and rather deliver therapy to the identified anddisplayed target regions 440.

In some embodiments, an audible signal, a tactile signal, or acombination thereof can be combined with the representation 400 to alertthe user of a location of the neuromodulation assembly 230. For example,the audible signal and/or the tactile signal can alert the user when oneor more energy delivery elements 260 of the neuromodulation assembly 230are located at an identified avoidance region 460 or alternatively at anidentified target region 440. Alternatively, the audible signal and/orthe tactile signal can include multiple signals wherein each signal(e.g., a tone, a vibration, repetition of the signal, etc.) correspondsto a particular energy delivery element 260 positioned at a particularregion. Using a multi-electrode catheter such as catheter 210, theclinician may operate console 295 to test each energy delivery element260 individually for a signal indicating the potential risk or benefitof administering neuromodulation energy at each element's currentlocation. For example, a first signal can correspond to an energydelivery element 260 located within an avoidance region 460, a secondsignal can correspond to a second energy delivery element 260 locatedwithin a potential region 450, and a third signal can correspond to athird energy delivery element 260 located within a target region 440.Similar to the displayed indicators, the audible signals and/or thetactile signals can be transmitted to the user in real-time as theneuromodulation assembly 230 is being positioned regardless of whetherthe location of the neuromodulation assembly 230 is visible onrepresentation 400 in real-time. In certain embodiments, only visualindicators are displayed on the representation 400, only audible signalsare transmitted to the user, or only tactile signals are transmitted tothe user.

FIG. 5 is a partially schematic illustration of a neuromodulation system500 (“system 500”) configured in accordance with another embodiment ofthe present technology. Certain features of system 500 are generallysimilar to other embodiments of the present technology described herein.The system 500 is different than the system 200 in that the transmitter245 is carried by a separate catheter or guidewire 555. In theillustrated embodiment, the sensor 240 is at the distal-most end (e.g.,tip) of the distal portion 220 b and the transmitter is disposed along alength of the wire 555. In other embodiments, the sensor 240 can beelsewhere along a length of the distal portion 220 b (e.g., on theneuromodulation assembly 230) and/or the transmitter 245 can be at thedistal-most end (e.g., tip) of the guidewire 555. The shaft 220 and theguidewire 555 can be integrated into a single neuromodulation catheter210 or, alternatively, they can be in separate components.

In other embodiments, the transmitter 245 can be at the distal portion220 b of the shaft 220 instead of the sensor, and the sensor 240 can becarried by the guidewire 555. In embodiments where the neuromodulationcatheter 210 includes more than one sensor 240 and/or more than onetransmitter 245, some of the sensors and/or some of the transmitters canbe carried by the distal portion 220 b of the shaft 220 and others canbe carried by the guidewire 555. In other embodiments, the sensor 240can be mounted on a portion of a guide catheter that is insertable intothe vessel receiving neuromodulation treatment.

FIG. 6 is a side view of the distal portion of the neuromodulationassembly 230 and guidewire 555 of FIG. 5 positioned within a bloodvessel in accordance with an embodiment of the present technology. Asmentioned above, the sensor 240 can be coupled to one of the shaft 220or the guidewire 555 while the transmitter 245 is coupled to the other.As such, the sensor 240 and the transmitter 245 can be deliveredindependently of each other.

In the illustrated embodiment, the sensor 240 is coupled to shaft 220and delivered through the guide catheter 320 with the neuromodulationassembly 230 to a first position along the vessel (e.g., renal arteryRA). Once catheter 210 is positioned, the guidewire 555 with thetransmitter 245 is delivered through the guide catheter 320 to a secondposition proximate the first position. For purposes of clarity, FIG. 6shows neuromodulation assembly 230 being not fully deployed within theblood vessel, and guidewire 555 is disposed alongside assembly 230. Itis expected that in a typical deployment, neuromodulation assembly 230is fully deployed within the blood vessel such that each energy deliveryelement 260 contacts the vessel wall to the extent possible, andguidewire 555 is disposed within assembly 230. The user can activate thesensor 240 to detect one or more hemodynamic parameters at the firstposition and can activate the transmitter 245 to send the location ofthe neuromodulation assembly 230 to the receiver 287. As described abovewith reference to FIGS. 2 and 3, the system 500 identifies whether eachenergy delivery element 260 is positioned at an identified target regionor an identified avoidance region. If an energy delivery element 260 ispositioned at an identified target region as illustrated on userinterface 297, the user can deliver neuromodulation therapy through thatelement. If an energy delivery element 260 is positioned near anidentified avoidance region (e.g., near stenosis 351, ostium 310, orbifurcation 315) the user can skip delivering neuromodulation therapythrough that element and/or re-position the neuromodulation assembly 230and the guidewire 555 to identify one or more target regions in thevessel. Alternatively, the user can reposition the transmitter 245adjacent each of energy delivery elements 260 a-g to determine if anenergy delivery element 260 is near an identified target region.

As illustrated in FIG. 6, the sensor 240 is located distal to energydelivery element 260 g and the transmitter 245 is located substantiallyadjacent to energy delivery element 260 f in the vessel. In otherembodiments, the sensor 240 can be located proximal to at least oneenergy delivery element 260 and the transmitter 245 can be locatedsubstantially adjacent to, proximal to, or distal to another energydelivery element 260. In further embodiments, the guidewire 555 can bedelivered to a first position in the vessel (e.g., renal artery RA)before the neuromodulation assembly 230. For example, if the CFD modelof the patient's vessel was generated before the transmitter 245 wasdelivered, such as during a previous procedure or as part of a priorpositioning, the user may have previously identified a desired targetlocation to deliver neuromodulation therapy. In this embodiment, theuser can activate the transmitter 245 to locate the desired targetlocation and position an energy delivery element of the neuromodulationassembly 230 at the desired location.

FIGS. 7-9 are anatomic and conceptual side views, cross-sectional views,and exploded views of a blood vessel illustrating a variety ofphysiologic and pathologic features. Although the configuration of ablood vessel can have many variations and/or a blood vessel can havelocal flow abnormalities, FIGS. 7-9 are shown for illustrative purposesand are not intended to exaggerate or limit the number, location,configurations and/or local flow abnormalities that may occur in a bloodvessel. As discussed above, delivering perivascular neuromodulationtherapy to an identified avoidance region (e.g., a certain location withone or more physiologic features, pathologic features, and/or flowabnormalities) may result in an unwanted event. Accordingly, the method100, systems 200, 500, and embodiments thereof can assist clinicians inavoiding such undesirable regions while also guiding users to desiredtarget regions.

As illustrated in FIG. 7, a main vessel 705 branches at a bifurcation315 into two branches including a right branch 712 and a left branch716. At the bifurcation 315, the branched vessels form a carina at thevessel wall (shown in detailed view). A lumen 710 extends through themain vessel 705 and divides into each branch as a right lumen 714 and aleft lumen 718. Blood can flow through the lumen 710 and can split atthe bifurcation 315 into right flow 733 and left flow 732. Throughlinear (e.g., straight) portions of the vessel having a healthy lumen(e.g., a smooth wall and a normal inner diameter to allow blood to flowwithout disturbance), blood flow is often laminar and impartsphysiologic shear stress (e.g., hemodynamic stress) on the vessel wall.Such wall shear stress (WSS) can be measured as force per unit areaexerted on the vessel wall and can be affected by blood viscosity andblood flow. Physiologic (e.g., healthy) WSS is about 1 to about 7dynes/cm² in the venous system and about 10 to about 15 dynes/cm² in thearterial system. The split flow into the right branch 712 and the leftbranch 716 places relatively high wall shear stress (HWSS) of about 27dynes/cm² or greater on the vessel wall at the bifurcation 315. Forexample, abrupt geometric changes in the vessel wall, such as thebifurcation 315, are subject to HWSS. Furthermore, when flowtrajectories change and blood contacts the vessel wall in a non-laminarmanner, the blood flow can become turbulent and/or form eddy currents735 as illustrated in region 730 of FIG. 7. For example, eddy currents735 can reduce normal wall shear stress to a relatively low wall shearstress (LWSS), such as about 12.6 dynes/cm² or less. These areas of LWSSoften occur distal to abrupt geometric changes (e.g., bifurcation 315)and/or adjacent to areas of HWSS. In addition, wall shear stress at acertain location in the vessel can vary, for example, having both HWSSand LWSS at a portion of the vessel (i.e., at the bifurcation 315 or atapered region 760).

In addition to the above physiologic changes in vascular geometry, bloodflow can also be altered by pathological events, such as changes in thevessel wall. For example, portions of the vessel wall that havethickened such as at a stenosis 351 impinge the laminar flow 754 inregion 750. As illustrated, the left lumen 718 narrows at stenosis 351,resulting in laminar flow 754 becoming turbulent flow 756 along thedistal portion of the region of impinged flow 750. Vascularcalcification 720 occurs by formation and/or deposit of calcium 727 inthe vessel wall. While calcium deposits can be located in the intima 721and/or adventitia 723, deposits are most commonly found in the media725. A portion of the vessel wall having a calcification 720 (e.g.,calcium deposits) is less elastic, having an impaired ability to respondto changes in blood flow, blood pressure, etc. compared to anon-calcified region.

As illustrated in FIGS. 8 and 9, the vessel wall can have other diseasesthat can result in an unwanted event in response to delivery ofneuromodulation therapy. For example, FIG. 8 illustrates a main vessel810 which branches into a left branch 820 and a right branch 825 havingfibromuscular dysplasia in region 830. A lumen 840 extends from the mainvessel 810 into the left branch 820 and through the region 830 havingfibromuscular dysplasia. Referring to enlarged sectional view 860,fibromuscular dysplasia causes abnormal thickening of the vessel walls850. While not intending to be limiting, FIG. 8 illustrates multi-focaltype fibromuscular dysplasia, as distinguished from focal andadventitial types. Fibromuscular dysplasia can affect many differentvessels; however the most common vessels include carotid arteries,vertebral arteries, renal arteries, and arteries coupled to arms, legs,and intestines.

The vessel wall can also be altered by the formation of an aneurysm,which is a localized dilation or ballooning of the vessel wall that maybe associated with hypertension and/or may occur at weak portions of thevessel wall. Aneurysms are often classified by their location, forexample, arterial, venous, cardiac, coronary, aorta, brain, legs,kidneys, and capillaries. As illustrated in FIG. 9, main vessel 905 hasa lumen 910 extending from a proximal portion 905 a through a distalportion 905 b. An aneurysm 920 is located between the proximal portion905 a and the distal portion 905 b. Referring to enlarged sectional view925, the aneurysm 920 includes a large lumen 930 (e.g., extending fromthe lumen 910), an outer wall 940 a, and an inner wall 940 b. While notintending to be limiting, FIG. 9 illustrates a saccular aneurysm 920,one of several types of aneurysms including fusiform and microaneurysms.

FIG. 10 (with additional reference to FIGS. 2-6) illustrates modulatingrenal nerves with a neuromodulation catheter described herein inaccordance with an additional embodiment of the present technology. Theneuromodulation catheter 210 provides access to the renal plexus RPthrough an intravascular path P, such as a percutaneous access region inthe femoral (illustrated), brachial, radial, or axillary artery to atargeted treatment region within a respective renal artery RA. Bymanipulating the proximal portion 220 a of the shaft 220 from outsidethe intravascular path P, a clinician may advance the shaft 220 throughthe sometimes tortuous intravascular path P and remotely manipulate thedistal portion 220 b (FIGS. 2-6) of the shaft 220. In the embodimentillustrated in FIG. 10, the neuromodulation assembly 230 is deliveredintravascularly to the treatment region using a guidewire 1010 in an OTWtechnique. At the treatment region, the guidewire 1010 can be at leastpartially withdrawn or removed, and the neuromodulation assembly 230 cantransform or otherwise be moved to a deployed arrangement for deliveringenergy at the treatment region. In other embodiments, theneuromodulation assembly 230 may be delivered to the treatment regionwithin a guide sheath (not shown) with or without using the guidewire1010. When the neuromodulation assembly 230 is at the target region, theguide sheath, if used, may be at least partially withdrawn or retractedsuch that the neuromodulation assembly 230 can transform into thedeployed configuration. In still other embodiments, the shaft 220 itselfmay be steerable such that the neuromodulation assembly 230 may bedelivered to the treatment region without the aid of the guidewire 1010and/or a guide sheath.

In addition to the method 100, systems 200, 500, and embodiments thereofdescribed herein regarding assessing hemodynamics for optimizingdelivery of neuromodulation therapy, image guidance, e.g., computedtomography (CT), fluoroscopy, intravascular ultrasound (IVUS), opticalcoherence tomography (OCT), intracardiac echocardiography (ICE), oranother suitable guidance modality, or combinations thereof, may alsoaid the clinician's positioning and manipulation of the neuromodulationcatheter 210 in accordance with the present technology. For example, afluoroscopy system (e.g., including a flat-panel detector, x-ray, orc-arm) can be rotated to accurately visualize and identify the targettreatment region. In other embodiments, the treatment region can bedetermined using IVUS, OCT, and/or other suitable image mappingmodalities that can correlate the target treatment region with anidentifiable anatomical structure (e.g., a spinal feature) and/or aradiopaque ruler (e.g., positioned under or on the patient) beforedelivering the neuromodulation assembly 230. Further, in someembodiments, image guidance components (e.g., IVUS, OCT) may beintegrated with the neuromodulation catheter 210 and/or run in parallelwith the neuromodulation catheter 210 to provide image guidance duringpositioning of the neuromodulation assembly 230. For example, imageguidance components (e.g., IVUS or OCT) can be coupled to theneuromodulation assembly 230 to provide three-dimensional images of thevasculature proximate the target region to facilitate positioning ordeploying the neuromodulation assembly 230 within the target vessel. Asdescribed above, the method 100, systems 200, 500, and embodimentsthereof can include determining the location of avoidance regions and/ortarget regions for delivering neuromodulation therapy and transmittinglocation information to the user. The image guidance modalitiesdescribed herein can be used in conjunction with methods, systems, andembodiments of the present technology to provide location information ofthe neuromodulation catheter 210 to the user in real-time.

Energy from the electrodes 260 (FIGS. 2-6) and/or other energy deliveryelements may then be applied to identified target tissue to induce oneor more desired neuromodulating effects on localized regions of therenal artery RA and adjacent perivascular regions of the renal plexusRP, which lay intimately within, adjacent to, or in close proximity tothe adventitia of the renal artery RA. The purposeful application of theenergy may achieve neuromodulation along all or at least a portion ofthe renal plexus RP. The neuromodulating effects are generally afunction of, at least in part, power, time, contact between the energydelivery elements and the vessel wall, and blood flow through thevessel. The neuromodulating effects may include denervation, thermalablation, and/or non-ablative thermal alteration or damage (e.g., viasustained heating and/or resistive heating). Desired thermal heatingeffects may include raising the temperature of target neural fibersabove a desired threshold to achieve non-ablative thermal alteration, orabove a higher temperature to achieve ablative thermal alteration. Forexample, the target temperature may be above body temperature (e.g.,approximately 37° C.) but less than about 45° C. for non-ablativethermal alteration, or the target temperature may be about 45° C. orhigher for the ablative thermal alteration. Desired non-thermalneuromodulation effects may include altering the electrical signalstransmitted in a nerve.

Hypothermic effects may also provide neuromodulation. For example, acryotherapeutic applicator may be used to cool tissue at a target regionto provide therapeutically-effective direct cell injury (e.g.,necrosis), vascular injury (e.g., starving the cell from nutrients bydamaging supplying blood vessels), and sublethal hypothermia withsubsequent apoptosis. Exposure to cryotherapeutic cooling can causeacute cell death (e.g., immediately after exposure) and/or delayed celldeath (e.g., during tissue thawing and subsequent hyperperfusion).Embodiments of the present technology can include cooling a structure ator near an inner surface of a renal artery wall such that proximate(e.g., adjacent) tissue is effectively cooled to a depth wheresympathetic renal nerves reside. For example, the cooling structure iscooled to the extent that it causes therapeutically effective, cryogenicrenal-nerve modulation. Sufficiently cooling at least a portion of asympathetic renal nerve is expected to slow or potentially blockconduction of neural signals to produce a prolonged or permanentreduction in renal sympathetic activity.

As illustrated in FIG. 11, at least a portion of the CFD model can begenerated using systems 200 and 500, device 1100, and environment 1200described below in accordance with the present technology. For example,the CFD workflow can, in part, be performed by computer 1110 configuredto execute instructions (e.g., one or more than one softwareapplications 1164 and 1166 for facilitating operation of the CFDworkflow) for generating the CFD model. In some embodiments, the CFDmodel can be saved to and/or stored at one or more servers 1220 (e.g., acentral server) with reference to FIG. 12.

FIG. 11 is a block diagram illustrating an overview of devices on whichsome implementations of the present technology can operate. The devicescan comprise hardware components of a device 1100 for analyzing thepatient's imaging data and hemodynamic parameters, comparing one or moreof the patient's hemodynamic parameters and/or optimized parametersagainst a threshold hemodynamic parameter, and providing arecommendation of whether to deliver neuromodulation therapy at alocation in a vessel. The device 1100, for example, can be incorporatedinto the console 295 described above with respect to FIG. 2.

The device 1100 can include, for example, one or more input devices 1120providing input to a central processing unit (“CPU”; processor) 1110,notifying the CPU 1110 of actions. The actions are typically mediated bya hardware controller that interprets the signals received from theinput device and communicates the information to the CPU 1110 using acommunication protocol. The input devices 1120 include, for example, areceiver for receiving signals from a monitoring device (e.g., thesensor 240 and/or the transmitter 245 described with reference to FIGS.2-6), a mouse, a keyboard, a touchscreen, an infrared sensor, atouchpad, a wearable input device, a camera- or image-based inputdevice, a microphone, and/or other user input devices.

The CPU 1110 can be a single processing unit or multiple processingunits in a device or distributed across multiple devices. CPU 1110 canbe coupled to other hardware devices, for example, with the use of abus, such as a PCI bus or SCSI bus. The CPU 1110 can communicate with ahardware controller for devices, such as a display 1130. The display1130, which can be the display 297 of the console 295 (FIG. 2), can beused to display text and graphics. In some examples, the display 1130provides graphical and textual visual information to the user, such asinformation related to one or more of the patient's hemodynamicparameters (e.g., individual and compared to threshold hemodynamicparameters), a summary of data detected by one or more sensors 240and/or transmitters 245 coupled to the device 1100, and/or othersuitable information. In some implementations, the display 1130 includesthe input device as part of the display, such as when the input deviceis a touchscreen or is equipped with an eye direction monitoring system.In some implementations, the display 1130 is separate from the inputdevice 1120. Examples of display devices are: an LCD display screen, anLED display screen, a projected, holographic, or augmented realitydisplay (such as a heads-up display device or a head-mounted device),and so on. Other input/output (I/O) devices 1140 can also be coupled tothe processor, such as a network card, video card, audio card, USB,firewire or other external device, camera, printer, speakers, CD-ROMdrive, DVD drive, disk drive, or Blu-Ray device.

In some implementations, the device 1100 also includes a communicationdevice capable of communicating wirelessly or wire-based with a networknode. The communication device can communicate with another device or aserver through a network using, for example, TCP/IP protocols. Device1100 can utilize the communication device to distribute operationsacross multiple network devices.

The device 1100 can execute embodiments of blocks 110, 120, 130, 140 and150 of method 100 described above with respect to FIG. 1. In order toexecute these embodiments, the CPU 1110 can be configured to have accessto a memory 1150. A memory includes one or more of various hardwaredevices for volatile and non-volatile storage, and can include bothread-only and writable memory. For example, a memory 1150 can includerandom access memory (RAM), CPU registers, read-only memory (ROM), andwritable non-volatile memory, such as flash memory, hard drives, floppydisks, CDs, DVDs, magnetic storage devices, tape drives, device buffers,and so forth. A memory is not a propagating signal divorced fromunderlying hardware; a memory is thus non-transitory. The memory 1150can include program memory 1160 for storing programs and software, suchas an operating system 1162, a hemodynamic parameter analysis program1164, and other application programs 1166. The hemodynamic parameteranalysis program 1164, for example, can include one or more algorithmsfor analyzing various indices related to one or more hemodynamicparameters, providing a hemodynamic parameter summary or report, orother information related to delivering neuromodulation therapy to thepatient based on hemodynamic parameters. The memory 1150 can alsoinclude data memory 1170 including sensed and/or recorded data from oneor more of the sensors, patient data, algorithms related to hemodynamicparameter analysis, configuration data, settings, user options orpreferences, etc., which can be provided to the program memory 1160 orany element of the device 1100.

Some implementations can be operational with numerous other generalpurpose or special purpose computing system environments orconfigurations. Examples of well-known computing systems, environments,and/or configurations that may be suitable for use with the technologyinclude, but are not limited to, personal computers, server computers,handheld or laptop devices, cellular telephones, wearable electronics,tablet devices, multiprocessor systems, microprocessor-based systems,set-top boxes, programmable consumer electronics, network PCs,minicomputers, mainframe computers, distributed computing environmentsthat include any of the above systems or devices, or the like.

FIG. 12 is a block diagram illustrating an overview of an environment1200 in which some implementations of the disclosed technology canoperate. The environment 1200 can include one or more client computingdevices 1205A-D (identified collectively as “client computing devices1205”), examples of which can include the device 1100 of FIG. 11. Theclient computing devices 1205 can operate in a networked environmentusing logical connections through a network 1230 to one or more remotecomputers, such as a server computing device 1210.

In some implementations, server 1210 can be an edge server that receivesclient requests and coordinates fulfillment of those requests throughother servers, such as servers 1220A-C. The server computing devices(not shown) can comprise computing systems, such as device 1100 (FIG.11). Though each server computing device (not shown) can logically be asingle server, the server computing devices (not shown) can each be adistributed computing environment encompassing multiple computingdevices located at the same or at geographically disparate physicallocations. In some implementations, each server 1220 corresponds to agroup of servers.

The client computing devices 1205 and the server computing devices 1210and 1220 can each act as a server or client to other server/clientdevices. The server 1210 can connect to a database 1215. The servers1220A-C can each connect to corresponding databases 1225A-C. Asdiscussed above, each server 1220 can correspond to a group of servers,and each of these servers can share a database or can have their owndatabase. The databases 1215 and 1225 can warehouse (e.g., store)information such as raw data (e.g., related to patient hemodynamicparameters, three-dimensional representations, CFD representations,representations), algorithms (e.g., deriving hemodynamic parameters,digital three-dimensional representations, CFD representations,representations), other patient information, and/or other informationnecessary for the implementation of the systems and methods describedabove with respect to FIGS. 1-11. Though the databases 1215 and 1225 aredisplayed logically as single units, the databases 1215 and 1225 caneach be a distributed computing environment encompassing multiplecomputing devices, can be located within their corresponding server, orcan be located at the same or at geographically disparate physicallocations.

The network 1230 can be a local area network (LAN) or a wide areanetwork (WAN), but can also be other wired or wireless networks. Thenetwork 1230 may be the Internet or some other public or privatenetwork. The client computing devices 1205 can be connected to thenetwork 1230 through a network interface, such as by wired or wirelesscommunication. While the connections between the server 1210 and servers1220 are shown as separate connections, these connections can be anykind of local, wide area, wired, or wireless network, including thenetwork 1230 or a separate public or private network.

III. Renal Neuromodulation

Renal neuromodulation is the partial or complete incapacitation or othereffective disruption of nerves of the kidneys (e.g., nerves terminatingin the kidneys or in structures closely associated with the kidneys). Inparticular, renal neuromodulation can include inhibiting, reducing,and/or blocking neural communication along neural fibers (e.g., efferentand/or afferent neural fibers) of the kidneys. Such incapacitation canbe long-term (e.g., permanent or for periods of months, years, ordecades) or short-term (e.g., for periods of minutes, hours, days, orweeks). Renal neuromodulation is expected to contribute to the systemicreduction of sympathetic tone or drive and/or to benefit at least somespecific organs and/or other bodily structures innervated by sympatheticnerves. Accordingly, renal neuromodulation is expected to be useful intreating clinical conditions associated with systemic sympatheticoveractivity or hyperactivity, particularly conditions associated withcentral sympathetic overstimulation. For example, renal neuromodulationis expected to efficaciously treat hypertension, heart failure, acutemyocardial infarction, metabolic syndrome, insulin resistance, diabetes,left ventricular hypertrophy, chronic and end stage renal disease,inappropriate fluid retention in heart failure, cardio-renal syndrome,polycystic kidney disease, polycystic ovary syndrome, osteoporosis,erectile dysfunction, and sudden death, among other conditions.

Renal neuromodulation can be electrically-induced, thermally-induced,chemically-induced, or induced in another suitable manner or combinationof manners at one or more suitable target regions during a treatmentprocedure. The target region can be within or otherwise proximate to arenal lumen (e.g., a renal artery, a ureter, a renal pelvis, a majorrenal calyx, a minor renal calyx, or another suitable structure), andthe treated tissue can include perivascular tissue (at least proximateto a wall of the renal lumen). For example, with regard to a renalartery, a treatment procedure can include modulating nerves in the renalplexus, which lay intimately within or adjacent to the adventitia of therenal artery.

Renal neuromodulation can include a cryotherapeutic treatment modalityalone or in combination with another treatment modality. Cryotherapeutictreatment can include cooling tissue at a target region in a manner thatmodulates neural function. For example, sufficiently cooling at least aportion of a sympathetic renal nerve can slow or potentially blockconduction of neural signals to produce a prolonged or permanentreduction in renal sympathetic activity. This effect can occur as aresult of cryotherapeutic tissue damage, which can include, for example,direct cell injury (e.g., necrosis), vascular or luminal injury (e.g.,starving cells from nutrients by damaging supplying blood vessels),and/or sublethal hypothermia with subsequent apoptosis. Exposure tocryotherapeutic cooling can cause acute cell death (e.g., immediatelyafter exposure) and/or delayed cell death (e.g., during tissue thawingand subsequent hyperperfusion). Neuromodulation using a cryotherapeutictreatment in accordance with embodiments of the present technology caninclude cooling a structure proximate an inner surface of a body lumenwall such that tissue is effectively cooled to a depth where sympatheticrenal nerves reside. For example, in some embodiments, a coolingassembly of a cryotherapeutic device can be cooled to the extent that itcauses therapeutically-effective, cryogenic renal neuromodulation. Inother embodiments, a cryotherapeutic treatment modality can includecooling that is not configured to cause neuromodulation. For example,the cooling can be at or above cryogenic temperatures and can be used tocontrol neuromodulation via another treatment modality (e.g., to protecttissue from neuromodulating energy).

Renal neuromodulation can include an electrode-based or transducer-basedtreatment modality alone or in combination with another treatmentmodality. Electrode-based or transducer-based treatment can includedelivering electricity and/or another form of energy to tissue at atreatment location to stimulate and/or heat the tissue in a manner thatmodulates neural function. For example, sufficiently stimulating and/orheating at least a portion of a sympathetic renal nerve can slow orpotentially block conduction of neural signals to produce a prolonged orpermanent reduction in renal sympathetic activity. A variety of suitabletypes of energy can be used to stimulate and/or heat tissue at atreatment location. For example, neuromodulation in accordance withembodiments of the present technology can include delivering RF energy,pulsed electrical energy, microwave energy, optical energy, focusedultrasound energy (e.g., high-intensity focused ultrasound energy), oranother suitable type of energy alone or in combination. An electrode ortransducer used to deliver this energy can be used alone or with otherelectrodes or transducers in a multi-electrode or multi-transducerarray. Furthermore, the energy can be applied from within the body(e.g., within the vasculature or other body lumens in a catheter-basedapproach) and/or from outside the body (e.g., via an applicatorpositioned outside the body). Furthermore, energy can be used to reducedamage to non-targeted tissue when targeted tissue adjacent to thenon-targeted tissue is subjected to neuromodulating cooling.

Neuromodulation using focused ultrasound energy (e.g., high-intensityfocused ultrasound energy) can be beneficial relative to neuromodulationusing other treatment modalities. Focused ultrasound is an example of atransducer-based treatment modality that can be delivered from outsidethe body. Focused ultrasound treatment can be performed in closeassociation with imaging (e.g., magnetic resonance, computed tomography,fluoroscopy, ultrasound (e.g., intravascular or intraluminal), opticalcoherence tomography, or another suitable imaging modality). Forexample, imaging can be used to identify an anatomical position of atreatment location (e.g., as a set of coordinates relative to areference point). The coordinates can then be entered into a focusedultrasound device configured to change the power, angle, phase, or othersuitable parameters to generate an ultrasound focal zone at the locationcorresponding to the coordinates. The focal zone can be small enough tolocalize therapeutically-effective heating at the treatment locationwhile partially or fully avoiding potentially harmful disruption ofnearby structures. To generate the focal zone, the ultrasound device canbe configured to pass ultrasound energy through a lens, and/or theultrasound energy can be generated by a curved transducer or by multipletransducers in a phased array (curved or straight).

Heating effects of electrode-based or transducer-based treatment caninclude ablation and/or non-ablative alteration or damage (e.g., viasustained heating and/or resistive heating). For example, a treatmentprocedure can include raising the temperature of target neural fibers toa target temperature above a first threshold to achieve non-ablativealteration, or above a second, higher threshold to achieve ablation. Thetarget temperature can be higher than about body temperature (e.g.,about 37° C.) but less than about 45° C. for non-ablative alteration,and the target temperature can be higher than about 45° C. for ablation.Heating tissue to a temperature between about body temperature and about45° C. can induce non-ablative alteration, for example, via moderateheating of target neural fibers or of vascular or luminal structuresthat perfuse the target neural fibers. In cases where vascularstructures are affected, the target neural fibers can be deniedperfusion resulting in necrosis of the neural tissue. Heating tissue toa target temperature higher than about 45° C. (e.g., higher than about70° C.) can induce ablation, for example, via substantial heating oftarget neural fibers or of vascular or luminal structures that perfusethe target fibers. In some patients, it can be desirable to heat tissueto temperatures that are sufficient to ablate the target neural fibersor the vascular or luminal structures, but that are less than about 40°C. (e.g., less than about 95° C., less than about 90° C., or less thanabout 85° C.).

Renal neuromodulation can include a chemical-based treatment modalityalone or in combination with another treatment modality. Neuromodulationusing chemical-based treatment can include delivering one or morechemicals (e.g., drugs or other agents) to tissue at a treatmentlocation in a manner that modulates neural function. The chemical, forexample, can be selected to affect the treatment location generally orto selectively affect some structures at the treatment location overother structures. The chemical, for example, can be guanethidine,ethanol, phenol, a neurotoxin, or another suitable agent selected toalter, damage, or disrupt nerves. A variety of suitable techniques canbe used to deliver chemicals to tissue at a treatment location. Forexample, chemicals can be delivered via one or more needles originatingoutside the body or within the vasculature or other body lumens. In anintravascular example, a catheter can be used to intravascularlyposition a therapeutic element including a plurality of needles (e.g.,micro-needles) that can be retracted or otherwise blocked beforedeployment. In other embodiments, a chemical can be introduced intotissue at a treatment location via simple diffusion through a body lumenwall, electrophoresis, or another suitable mechanism. Similar techniquescan be used to introduce chemicals that are not configured to causeneuromodulation, but rather to facilitate neuromodulation via anothertreatment modality.

IV. Related Anatomy and Physiology

As noted previously, the sympathetic nervous system (SNS) is a branch ofthe autonomic nervous system along with the enteric nervous system andparasympathetic nervous system. It is always active at a basal level(called sympathetic tone) and becomes more active during times ofstress. Like other parts of the nervous system, the sympathetic nervoussystem operates through a series of interconnected neurons. Sympatheticneurons are frequently considered part of the peripheral nervous system(PNS), although many lie within the central nervous system (CNS).Sympathetic neurons of the spinal cord (which is part of the CNS)communicate with peripheral sympathetic neurons via a series ofsympathetic ganglia. Within the ganglia, spinal cord sympathetic neuronsjoin peripheral sympathetic neurons through synapses. Spinal cordsympathetic neurons are therefore called presynaptic (or preganglionic)neurons, while peripheral sympathetic neurons are called postsynaptic(or postganglionic) neurons.

At synapses within the sympathetic ganglia, preganglionic sympatheticneurons release acetylcholine, a chemical messenger that binds andactivates nicotinic acetylcholine receptors on postganglionic neurons.In response to this stimulus, postganglionic neurons principally releasenoradrenaline (norepinephrine). Prolonged activation may elicit therelease of adrenaline from the adrenal medulla.

Once released, norepinephrine and epinephrine bind adrenergic receptorson peripheral tissues. Binding to adrenergic receptors causes a neuronaland hormonal response. The physiologic manifestations include pupildilation, increased heart rate, occasional vomiting, and increased bloodpressure. Increased sweating is also seen due to binding of cholinergicreceptors of the sweat glands.

The sympathetic nervous system is responsible for up- anddown-regulating many homeostatic mechanisms in living organisms. Fibersfrom the SNS innervate tissues in almost every organ system, providingat least some regulatory function to physiological features as diverseas pupil diameter, gut motility, and urinary output. This response isalso known as sympatho-adrenal response of the body, as thepreganglionic sympathetic fibers that end in the adrenal medulla (butalso all other sympathetic fibers) secrete acetylcholine, whichactivates the secretion of adrenaline (epinephrine) and to a lesserextent noradrenaline (norepinephrine). Therefore, this response thatacts primarily on the cardiovascular system is mediated directly viaimpulses transmitted through the sympathetic nervous system andindirectly via catecholamines secreted from the adrenal medulla.

Science typically looks at the SNS as an automatic regulation system,that is, one that operates without the intervention of consciousthought. Some evolutionary theorists suggest that the sympatheticnervous system operated in early organisms to maintain survival as thesympathetic nervous system is responsible for priming the body foraction. One example of this priming is in the moments before waking, inwhich sympathetic outflow spontaneously increases in preparation foraction.

1. The Sympathetic Chain

As shown in FIG. 13, the SNS provides a network of nerves that allowsthe brain to communicate with the body. Sympathetic nerves originateinside the vertebral column, toward the middle of the spinal cord in theintermediolateral cell column (or lateral horn), beginning at the firstthoracic segment of the spinal cord and are thought to extend to thesecond or third lumbar segments. Because its cells begin in the thoracicand lumbar regions of the spinal cord, the SNS is said to have athoracolumbar outflow. Axons of these nerves leave the spinal cordthrough the anterior rootlet/root. They pass near the spinal (sensory)ganglion, where they enter the anterior rami of the spinal nerves.However, unlike somatic innervation, they quickly separate out throughwhite rami connectors which connect to either the paravertebral (whichlie near the vertebral column) or prevertebral (which lie near theaortic bifurcation) ganglia extending alongside the spinal column.

In order to reach the target organs and glands, the axons should travellong distances in the body, and to accomplish this, many axons relaytheir message to a second cell through synaptic transmission. The endsof the axons link across a space, the synapse, to the dendrites of thesecond cell. The first cell (the presynaptic cell) sends aneurotransmitter across the synaptic cleft where it activates the secondcell (the postsynaptic cell). The message is then carried to the finaldestination.

In the SNS and other components of the peripheral nervous system, thesesynapses are made at regions called ganglia, discussed above. The cellthat sends its fiber is called a preganglionic cell, while the cellwhose fiber leaves the ganglion is called a postganglionic cell. Asmentioned previously, the preganglionic cells of the SNS are locatedbetween the first thoracic (T1) segment and third lumbar (L3) segmentsof the spinal cord. Postganglionic cells have their cell bodies in theganglia and send their axons to target organs or glands.

The ganglia include not just the sympathetic trunks but also thecervical ganglia (superior, middle and inferior), which sendssympathetic nerve fibers to the head and thorax organs, and the celiacand mesenteric ganglia (which send sympathetic fibers to the gut).

2. Innervation of the Kidneys

As FIG. 14 shows, the kidney is innervated by the renal plexus (RP),which is intimately associated with the renal artery. The renal plexus(RP) is an autonomic plexus that surrounds the renal artery and isembedded within the adventitia of the renal artery. The renal plexus(RP) extends along the renal artery until it arrives at the substance ofthe kidney. Fibers contributing to the renal plexus (RP) arise from theceliac ganglion, the superior mesenteric ganglion, the aorticorenalganglion and the aortic plexus. The renal plexus (RP), also referred toas the renal nerve, is predominantly comprised of sympatheticcomponents. There is no (or at least very minimal) parasympatheticinnervation of the kidney.

Preganglionic neuronal cell bodies are located in the intermediolateralcell column of the spinal cord. Preganglionic axons pass through theparavertebral ganglia (they do not synapse) to become the lessersplanchnic nerve, the least splanchnic nerve, first lumbar splanchnicnerve, second lumbar splanchnic nerve, and travel to the celiacganglion, the superior mesenteric ganglion, and the aorticorenalganglion. Postganglionic neuronal cell bodies exit the celiac ganglion,the superior mesenteric ganglion, and the aorticorenal ganglion to therenal plexus (RP) and are distributed to the renal vasculature.

3. Renal Sympathetic Neural Activity

Messages travel through the SNS in a bidirectional flow. Efferentmessages may trigger changes in different parts of the bodysimultaneously. For example, the sympathetic nervous system mayaccelerate heart rate; widen bronchial passages; decrease motility(movement) of the large intestine; constrict blood vessels; increaseperistalsis in the esophagus; cause pupil dilation, piloerection (goosebumps) and perspiration (sweating); and raise blood pressure. Afferentmessages carry signals from various organs and sensory receptors in thebody to other organs and, particularly, the brain.

Hypertension, heart failure, and chronic kidney disease are a few ofmany disease states that result from chronic activation of the SNS,especially the renal sympathetic nervous system. Chronic activation ofthe SNS is a maladaptive response that drives the progression of thesedisease states. Pharmaceutical management of therenin-angiotensin-aldosterone system (RAAS) has been a longstanding, butsomewhat ineffective, approach for reducing over-activity of the SNS.

As mentioned above, the renal sympathetic nervous system has beenidentified as a major contributor to the complex pathophysiology ofhypertension, states of volume overload (such as heart failure), andprogressive renal disease, both experimentally and in humans. Studiesemploying radiotracer dilution methodology to measure overflow ofnorepinephrine from the kidneys to plasma revealed increased renalnorepinephrine (NE) spillover rates in patients with essentialhypertension, particularly so in young hypertensive subjects, which inconcert with increased NE spillover from the heart, is consistent withthe hemodynamic profile typically seen in early hypertension andcharacterized by an increased heart rate, cardiac output, andrenovascular resistance. It is now known that essential hypertension iscommonly neurogenic, often accompanied by pronounced sympathetic nervoussystem overactivity.

Activation of cardiorenal sympathetic nerve activity is even morepronounced in heart failure, as demonstrated by an exaggerated increaseof NE overflow from the heart and the kidneys to plasma in this patientgroup. In line with this notion is the recent demonstration of a strongnegative predictive value of renal sympathetic activation on all-causemortality and heart transplantation in patients with congestive heartfailure, which is independent of overall sympathetic activity,glomerular filtration rate, and left ventricular ejection fraction.These findings support the notion that treatment regimens that aredesigned to reduce renal sympathetic stimulation have the potential toimprove survival in patients with heart failure.

Both chronic and end stage renal disease are characterized by heightenedsympathetic nervous activation. In patients with end stage renaldisease, plasma levels of norepinephrine above the median have beendemonstrated to be predictive for both all-cause death and death fromcardiovascular disease. This is also true for patients suffering fromdiabetic or contrast nephropathy. There is compelling evidencesuggesting that sensory afferent signals originating from the diseasedkidneys are major contributors to initiating and sustaining elevatedcentral sympathetic outflow in this patient group; this facilitates theoccurrence of the well-known adverse consequences of chronic sympatheticoveractivity, such as hypertension, left ventricular hypertrophy,ventricular arrhythmias, sudden cardiac death, insulin resistance,diabetes, and metabolic syndrome.

(i) Renal Sympathetic Efferent Activity

Sympathetic nerves to the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus and the renal tubules. Stimulation of therenal sympathetic nerves causes increased renin release, increasedsodium (Na⁺) reabsorption, and a reduction of renal blood flow. Thesecomponents of the neural regulation of renal function are considerablystimulated in disease states characterized by heightened sympathetictone and clearly contribute to the rise in blood pressure inhypertensive patients. The reduction of renal blood flow and glomerularfiltration rate as a result of renal sympathetic efferent stimulation islikely a cornerstone of the loss of renal function in cardio-renalsyndrome, which is renal dysfunction as a progressive complication ofchronic heart failure, with a clinical course that typically fluctuateswith the patient's clinical status and treatment. Pharmacologicstrategies to thwart the consequences of renal efferent sympatheticstimulation include centrally acting sympatholytic drugs, beta blockers(intended to reduce renin release), angiotensin converting enzymeinhibitors and receptor blockers (intended to block the action ofangiotensin II and aldosterone activation consequent to renin release)and diuretics (intended to counter the renal sympathetic mediated sodiumand water retention). However, the current pharmacologic strategies havesignificant limitations including limited efficacy, compliance issues,side effects and others.

(ii) Renal Sensory Afferent Nerve Activity

The kidneys communicate with integral structures in the central nervoussystem via renal sensory afferent nerves. Several forms of “renalinjury” may induce activation of sensory afferent signals. For example,renal ischemia, reduction in stroke volume or renal blood flow, or anabundance of adenosine enzyme may trigger activation of afferent neuralcommunication. As shown in FIGS. 15 and 16, this afferent communicationmight be from the kidney to the brain or might be from one kidney to theother kidney (via the central nervous system). These afferent signalsare centrally integrated and may result in increased sympatheticoutflow. This sympathetic drive is directed towards the kidneys, therebyactivating the RAAS and inducing increased renin secretion, sodiumretention, volume retention and vasoconstriction. Central sympatheticoveractivity also impacts other organs and bodily structures innervatedby sympathetic nerves such as the heart and the peripheral vasculature,resulting in the described adverse effects of sympathetic activation,several aspects of which also contribute to the rise in blood pressure.

The physiology therefore suggests that (i) modulation of tissue withefferent sympathetic nerves will reduce inappropriate renin release,salt retention, and reduction of renal blood flow, and that (ii)modulation of tissue with afferent sensory nerves will reduce thesystemic contribution to hypertension and other disease statesassociated with increased central sympathetic tone through its directeffect on the posterior hypothalamus as well as the contralateralkidney. In addition to the central hypotensive effects of afferent renaldenervation, a desirable reduction of central sympathetic outflow tovarious other sympathetically innervated organs such as the heart andthe vasculature is anticipated.

B. Additional Clinical Benefits of Renal Denervation

As provided above, renal denervation is likely to be valuable in thetreatment of several clinical conditions characterized by increasedoverall and particularly renal sympathetic activity such ashypertension, metabolic syndrome, insulin resistance, diabetes, leftventricular hypertrophy, chronic end stage renal disease, inappropriatefluid retention in heart failure, cardio-renal syndrome, and suddendeath. Since the reduction of afferent neural signals contributes to thesystemic reduction of sympathetic tone/drive, renal denervation mightalso be useful in treating other conditions associated with systemicsympathetic hyperactivity. Accordingly, renal denervation may alsobenefit other organs and bodily structures innervated by sympatheticnerves, including those identified in FIG. 13. For example, aspreviously discussed, a reduction in central sympathetic drive mayreduce the insulin resistance that afflicts people with metabolicsyndrome and Type II diabetics. Additionally, patients with osteoporosisare also sympathetically activated and might also benefit from thedown-regulation of sympathetic drive that accompanies renal denervation.

C. Achieving Intravascular Access to the Renal Artery

In accordance with the present technology, neuromodulation of a leftand/or right renal plexus (RP), which is intimately associated with aleft and/or right renal artery, may be achieved through intravascularaccess. As FIG. 17 shows, blood moved by contractions of the heart isconveyed from the left ventricle of the heart by the aorta. The aortadescends through the thorax and has branches into the left and rightrenal arteries. Below the renal arteries, the aorta bifurcates at theleft and right iliac arteries. The left and right iliac arteriesdescend, respectively, through the left and right legs and join the leftand right femoral arteries.

As FIG. 18 shows, the blood collects in veins and returns to the heart,through the femoral veins into the iliac veins and into the inferiorvena cava. The inferior vena cava branches into the left and right renalveins. Above the renal veins, the inferior vena cava ascends to conveyblood into the right atrium of the heart. From the right atrium, theblood is pumped through the right ventricle into the lungs, where it isoxygenated. From the lungs, the oxygenated blood is conveyed into theleft atrium. From the left atrium, the oxygenated blood is conveyed bythe left ventricle back to the aorta.

As will be described in greater detail later, the femoral artery may beaccessed and cannulated at the base of the femoral triangle justinferior to the midpoint of the inguinal ligament. A catheter may beinserted percutaneously into the femoral artery through this accessregion, passed through the iliac artery and aorta, and placed intoeither the left or right renal artery. This comprises an intravascularpath that offers minimally invasive access to a respective renal arteryand/or other renal blood vessels.

The wrist, upper arm, and shoulder region provide other locations forintroduction of catheters into the arterial system. For example,catheterization of either the radial, brachial, or axillary artery maybe utilized in select cases. Catheters introduced via these accesspoints may be passed through the subclavian artery on the left side (orvia the subclavian and brachiocephalic arteries on the right side),through the aortic arch, down the descending aorta and into the renalarteries using standard angiographic technique.

D. Properties and Characteristics of the Renal Vasculature

Since neuromodulation of a left and/or right renal plexus (RP) may beachieved in accordance with the present technology through intravascularaccess, properties and characteristics of the renal vasculature mayimpose constraints upon and/or inform the design of apparatus, systems,and methods for achieving such renal neuromodulation. Some of theseproperties and characteristics may vary across the patient populationand/or within a specific patient across time, as well as in response todisease states, such as hypertension, chronic kidney disease, vasculardisease, end-stage renal disease, insulin resistance, diabetes,metabolic syndrome, etc. These properties and characteristics, asexplained herein, may have bearing on the efficacy of the procedure andthe specific design of the intravascular device. Properties of interestmay include, for example, material/mechanical, spatial, fluiddynamic/hemodynamic, and/or thermodynamic properties.

As discussed previously, a catheter may be advanced percutaneously intoeither the left or right renal artery via a minimally invasiveintravascular path. However, minimally invasive renal arterial accessmay be challenging, for example, because as compared to some otherarteries that are routinely accessed using catheters, the renal arteriesare often extremely tortuous, may be of relatively small diameter,and/or may be of relatively short length. Furthermore, renal arterialatherosclerosis is common in many patients, particularly those withcardiovascular disease. Renal arterial anatomy also may varysignificantly from patient to patient, which further complicatesminimally invasive access. Significant inter-patient variation may beseen, for example, in relative tortuosity, diameter, length, and/oratherosclerotic plaque burden, as well as in the take-off angle at whicha renal artery branches from the aorta. Apparatus, systems, and methodsfor achieving renal neuromodulation via intravascular access, shouldaccount for these and other aspects of renal arterial anatomy and itsvariation across the patient population when minimally invasivelyaccessing a renal artery.

In addition to complicating renal arterial access, specifics of therenal anatomy also complicate establishment of stable contact betweenneuromodulatory apparatus and a luminal surface or wall of a renalartery. For example, navigation can be impeded by the tight space withina renal artery, as well as tortuosity of the artery. Furthermore,establishing consistent contact is complicated by patient movement,respiration, and/or the cardiac cycle because these factors may causesignificant movement of the renal artery relative to the aorta, and thecardiac cycle may transiently distend the renal artery (i.e. cause thewall of the artery to pulse).

Even after accessing a renal artery and facilitating stable contactbetween the neuromodulatory apparatus and a luminal surface of theartery, nerves in and around the adventitia of the artery should besafely modulated via the neuromodulatory apparatus. Effectively applyingthermal treatment from within a renal artery is non-trivial given thepotential clinical complications associated with such treatment. Forexample, the intima and media of the renal artery are highly vulnerableto thermal injury. As discussed in greater detail below, theintima-media thickness separating the vessel lumen from its adventitiameans that target renal nerves may be multiple millimeters distant fromthe luminal surface of the artery. Sufficient energy should be deliveredto or heat removed from the target renal nerves to modulate the targetrenal nerves without excessively cooling or heating the vessel wall tothe extent that the wall is frozen, desiccated, or otherwise potentiallyaffected to an undesirable extent. A potential clinical complicationassociated with excessive heating is thrombus formation from coagulatingblood flowing through the artery. Given that this thrombus may cause akidney infarct, thereby causing irreversible damage to the kidney,thermal treatment from within the renal artery should be appliedcarefully. Accordingly, the complex fluid mechanics and thermodynamicconditions present in the renal artery during treatment, particularlythose that may impact heat transfer dynamics at the treatment region,may be important in applying energy (e.g., heating thermal energy)and/or removing heat from the tissue (e.g., cooling thermal conditions)from within the renal artery.

The neuromodulatory apparatus should also be configured to allow foradjustable positioning and repositioning of the energy delivery elementwithin the renal artery since location of treatment may also impactclinical efficacy. For example, it may be tempting to apply a fullcircumferential treatment from within the renal artery given that therenal nerves may be spaced circumferentially around a renal artery. Insome situations, a full-circle lesion likely resulting from a continuouscircumferential treatment may be potentially related to renal arterystenosis. Therefore, the formation of more complex lesions along alongitudinal dimension of the renal artery and/or repositioning of theneuromodulatory apparatus to multiple treatment locations may bedesirable. It should be noted, however, that a benefit of creating acircumferential ablation may outweigh the potential of renal arterystenosis or the risk may be mitigated with certain embodiments or incertain patients and creating a circumferential ablation could be agoal. Additionally, variable positioning and repositioning of theneuromodulatory apparatus may prove to be useful in circumstances wherethe renal artery is particularly tortuous or where there are proximalbranch vessels off the renal artery main vessel, making treatment incertain locations challenging. Manipulation of a device in a renalartery should also consider mechanical injury imposed by the device onthe renal artery. Motion of a device in an artery, for example byinserting, manipulating, negotiating bends and so forth, may contributeto dissection, perforation, denuding intima, or disrupting the interiorelastic lamina.

V. Additional Examples

The following examples are illustrative of several embodiments of thepresent technology:

1. A method for evaluating a vessel for neuromodulation therapy, themethod comprising:

-   -   receiving, at a processor, digital data regarding        three-dimensional imaging of the vessel;    -   receiving, at the processor, hemodynamic data;    -   generating, at the processor, a computational fluid dynamics        (CFD) model of the vessel based at least in part on the imaging        data and the hemodynamic data;    -   identifying, with reference to the CFD model, avoidance regions        of the vessel for neuromodulation therapy, wherein the avoidance        regions include regions of at least one of flow separation, eddy        formation, flow impingement, low wall shear stress (WSS), or        high WSS gradients; and    -   displaying, on a user interface, a representation of the vessel        including visual markers indicating the avoidance regions.

2. The method of example 1 wherein receiving the three-dimensionalimaging data includes receiving three-dimensional imaging data of arenal artery, a pulmonary artery, a hepatic artery, a coronary artery,or an aorta.

3. The method of examples 1 or 2 wherein receiving the three-dimensionalimaging data of the vessel includes receiving three-dimensional imagingdata of a main vessel, at least one branch vessel of the main vessel, orat least one accessory vessel directly coupled to the at least one ofthe branch vessel or another vessel coupled to the main vessel.

4. The method of any one of examples 1-3, further comprising:

-   -   receiving location data from a neuromodulation catheter        regarding the position of the neuromodulation catheter in the        vessel; and    -   providing, via the processor, a recommendation to a user of        whether to proceed with neuromodulation therapy at the device        position based on the identified avoidance regions.

5. The method of any one of examples 1-4 wherein providing therecommendation via the processor comprises generating a signal to theuser indicative of the avoidance regions, wherein the signal includes anaudio signal, a visual signal, a tactile signal, or a combinationthereof.

6. The method of any one of examples 1-5 wherein displaying therepresentation of the vessel further comprises displaying indicators ofoptimal portions or acceptable portions of the vessel for deliveringneuromodulation therapy.

7. The method of any one of examples 1-6 wherein displaying therepresentation of the vessel further comprises:

-   -   displaying a first portion of the vessel on the representation;        and    -   displaying a second portion of the vessel on the representation,        wherein the second portion corresponds to one or more avoidance        regions of the vessel, and wherein the displayed first portion        has a lower resolution compared to the displayed second portion.

8. The method of any one of examples 1-7 wherein receiving thehemodynamic data comprises receiving blood pressure data, blood flowdata, blood impedance data, or a combination thereof.

9. The method of any one of examples 1-8 wherein receiving thehemodynamic data comprises receiving the pressure data and/or blood flowdata via a guidewire having a pressure sensor and/or a flow sensor.

10. The method of any one of examples 1-9 wherein receiving thehemodynamic data comprises:

-   -   receiving blood pressure data via an external pressure cuff;        and/or    -   receiving blood flow data via magnetic resonance imaging (MRI),        ultrasound Doppler shift flow meter, or a combination thereof.

11. The method of any one of examples 1-10 wherein receiving the digitaldata regarding three-dimensional imaging of the vessel comprisesreceiving data acquired using angiography, x-ray, computed tomography(CT), MM, or a combination thereof.

12. The method of any one of examples 1-11 wherein receiving hemodynamicdata comprises receiving blood pressure data and/or blood flow datameasured at a position within a main portion of the vessel having atleast generally laminar flow.

13. The method of any one of examples 1-12 wherein receiving hemodynamicdata comprises receiving blood pressure data and/or blood flow datameasured at a position within at least one branch vessel and/or at leastone accessory vessel.

14. The method of any one of examples 1-13 wherein providing therecommendation further comprises:

-   -   recommending avoiding neuromodulation therapy at one or more        portions of the vessel having at least one hemodynamic parameter        in the hemodynamic data that exceeds a threshold hemodynamic        parameter, and thereby indicates at least one local flow        abnormality.

15. The method of any one of examples 1-14 wherein identifying avoidanceregions of the vessel comprises identifying portions of the vessel at orproximate to an ostium, a carina, a taper region, a calcification, afibromuscular dysplasia, an aneurysm, a bifurcation, or a combinationthereof.

16. The method of any one of examples 1-15 wherein generating thecomputational fluid dynamic model of the vessel comprises applying ahemodynamic parameter derived from empirical data or conglomerate data.

17. A method of identifying a target neuromodulation therapy region in avessel of a human patient, the method comprising:

-   -   receiving, at a processor, digital data regarding        three-dimensional imaging of the vessel;    -   receiving, at the processor, hemodynamic data related to the        vessel;    -   generating, at the processor, a computational fluid dynamics        (CFD) representation of the vessel based at least in part on the        imaging data and the hemodynamic data, the computational fluid        dynamics representation including flow parameters;    -   identifying, via the processor, target regions of the vessel        suitable for neuromodulation therapy and avoidance regions of        the vessel less suitable for neuromodulation therapy; and    -   displaying, on a user interface, the CFD representation of the        vessel including visual indicia indicating the identified target        regions and the identified avoidance regions.

18. The method of example 17, further comprising:

-   -   delivering a neuromodulation catheter to the vessel of the human        patient;    -   monitoring a location of the neuromodulation catheter within the        vessel; and    -   indicating, via the user interface, the location of the        neuromodulation catheter relative to the identified target        regions and the identified avoidance regions of the vessel.

19. The method of example 17 or 18, further comprising providing, viathe user interface, a recommendation, made by the processor, of whetherto proceed with neuromodulation therapy at the current neuromodulationcatheter location within the vessel, the recommendation being based on acomparison between the current location of the neuromodulation catheterand the identified target regions and/or the identified avoidanceregions of the vessel.

20. The method of any one of examples 17-19 wherein the location of theneuromodulation catheter is monitored in real-time.

21. The method of any one of examples 17-20 wherein receiving thehemodynamic data related to the vessel comprises detecting at least oneof blood pressure or blood flow using a sensor disposed within thevessel.

22. The method of any one of examples 17-21 wherein identifying theavoidance regions comprises identifying portions of the vessel havinglow wall shear stress (WSS), high WSS, high WSS gradients, an ostium, acarina, a taper region, a calcification, a fibromuscular dysplasia, ananeurysm, a bifurcation, a region of blood flow separation, an eddy, aregion of impinged blood flow, a region of turbulent blood flow, aregion of secondary blood flow, or a combination thereof.

23. The method of any one of examples 17-22, further comprising applyingneuromodulation energy to at least one of the identified target regionsof the vessel, wherein the neuromodulation therapy comprises energydelivery, cryotherapy and/or chemical-based treatment.

24. The method of any one of examples 17-23 wherein receivinghemodynamic data related to the vessel comprises receiving at least oneof a blood pressure measurement or a blood flow measurement from asensor of the neuromodulation catheter.

25. A non-transitory computer readable memory storing instructions that,when executed by a processor of a computing device, cause the computingdevice to perform operations for identifying a target neuromodulationtherapy region in a blood vessel, the operations comprising:

-   -   receiving data regarding three-dimensional imaging of the        vessel;    -   receiving at least one of blood pressure data or blood flow data        related to the vessel;    -   generating a computational fluid dynamics (CFD) model of the        vessel based at least in part on the vessel imaging data and the        blood pressure and/or blood flow data;    -   identifying target regions of the vessel suitable for        neuromodulation therapy and avoidance regions of the vessel to        avoid during neuromodulation therapy, the identifying being        based on the CFD model of the vessel; and    -   displaying, on a user interface, a representation of the vessel        including visual markers indicating the identified target        regions and the identified avoidance regions.

26. A system for optimizing neuromodulation therapy in a renal bloodvessel of a human patient, the system comprising:

-   -   a neuromodulation catheter including—        -   an elongate shaft having a proximal portion and a distal            portion, wherein the shaft is configured to locate the            distal portion intravascularly at a treatment region within            the vessel of a human patient;        -   a neuromodulation assembly at the distal portion of the            shaft; and        -   at least one sensor at the distal portion of the shaft,            wherein the sensor is configured to transmit hemodynamic            data regarding the blood vessel;    -   a computing device having a memory and a processor, wherein the        memory stores instructions that, when executed by the processor,        cause the system to perform operations comprising—        -   receiving digital data regarding three-dimensional imaging            of the vessel;        -   receiving hemodynamic data from the sensor;        -   generating, at the processor, a computational fluid dynamics            (CFD) model of the vessel based at least in part on the            three-dimensional imaging of the vessel and the hemodynamic            data;        -   identifying target regions of the vessel suitable for            neuromodulation therapy and avoidance regions of the vessel            less suitable for neuromodulation therapy based on the CFD            model; and        -   displaying a representation of the vessel including visual            markers indicating the avoidance regions.

27. The system of example 26 wherein the sensor comprises at least oneof a blood pressure sensor or a blood flow sensor.

28. The system of example 26 or 27 wherein the neuromodulation catheterfurther comprises a transmitter at the distal portion of the shaft,wherein the transmitter is configured to communicate, to a receiver, thecurrent location of the neuromodulation assembly in the vessel.

VI. Conclusion

This disclosure is not intended to be exhaustive or to limit the presenttechnology to the precise forms disclosed herein. Although specificembodiments are disclosed herein for illustrative purposes, variousequivalent modifications are possible without deviating from the presenttechnology, as those of ordinary skill in the relevant art willrecognize. In some cases, well-known structures and functions have notbeen shown and/or described in detail to avoid unnecessarily obscuringthe description of the embodiments of the present technology. Althoughsteps of methods may be presented herein in a particular order, inalternative embodiments the steps may have another suitable order.Similarly, certain aspects of the present technology disclosed in thecontext of particular embodiments can be combined or eliminated in otherembodiments. For example, where a multi-electrode or multi-elementneuromodulation catheter is shown herein, a single-electrode orsingle-element neuromodulation catheter may be used instead.Furthermore, while advantages associated with certain embodiments mayhave been disclosed in the context of those embodiments, otherembodiments can also exhibit such advantages, and not all embodimentsneed necessarily exhibit such advantages or other advantages disclosedherein to fall within the scope of the present technology. Accordingly,this disclosure and associated technology can encompass otherembodiments not expressly shown and/or described herein.

Several implementations of the disclosed technology are described abovein reference to the figures. The computing devices on which thedescribed technology may be implemented can include one or more centralprocessing units, memory, input devices (e.g., keyboard and pointingdevices), output devices (e.g., display devices), storage devices (e.g.,disk drives), and network devices (e.g., network interfaces). The memoryand storage devices are computer-readable storage media that can storeinstructions that implement at least portions of the describedtechnology. In addition, the data structures and message structures canbe stored or transmitted via a data transmission medium, such as asignal on a communications link. Various communications links can beused, such as the Internet, a local area network, a wide area network,or a point-to-point dial-up connection. Thus, computer-readable mediacan comprise computer-readable storage media (e.g., “non-transitory”media) and computer-readable transmission media.

Throughout this disclosure, the singular terms “a,” “an,” and “the”include plural referents unless the context clearly indicates otherwise.Similarly, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the terms “comprising” and the like are used throughout this disclosureto mean including at least the recited feature(s) such that any greaternumber of the same feature(s) and/or one or more additional types offeatures are not precluded. Directional terms, such as “upper,” “lower,”“front,” “back,” “vertical,” and “horizontal,” may be used herein toexpress and clarify the relationship between various elements. It shouldbe understood that such terms do not denote absolute orientation.Reference herein to “one embodiment,” “an embodiment,” or similarformulations means that a particular feature, structure, operation, orcharacteristic described in connection with the embodiment can beincluded in at least one embodiment of the present technology. Thus, theappearances of such phrases or formulations herein are not necessarilyall referring to the same embodiment. Furthermore, various particularfeatures, structures, operations, or characteristics may be combined inany suitable manner in one or more embodiments.

I/We claim:
 1. A method for evaluating a vessel for neuromodulationtherapy, the method comprising: receiving, at a processor, digital dataregarding three-dimensional imaging of the vessel; receiving, at theprocessor, hemodynamic data regarding the vessel; generating, at theprocessor, a computational fluid dynamics (CFD) model of the vesselbased at least in part on the imaging data and the hemodynamic data;identifying, with reference to the CFD model, avoidance regions of thevessel for neuromodulation therapy, wherein the avoidance regionsinclude regions of at least one of flow separation, eddy formation, flowimpingement, low wall shear stress (WSS), or high WSS gradients; anddisplaying, on a user interface, a representation of the vesselincluding visual markers indicating the identified avoidance regions. 2.The method of claim 1 wherein the vessel is a renal artery, a pulmonaryartery, a hepatic artery, a coronary artery, or an aorta.
 3. The methodof claim 1 wherein the vessel is a main vessel, at least one branchvessel of the main vessel, or at least one accessory vessel directlycoupled to the at least one branch vessel or another vessel coupled tothe main vessel.
 4. The method of claim 1, further comprising: receivinglocation data from a neuromodulation catheter regarding the position ofthe neuromodulation catheter in the vessel; and providing, via theprocessor, a recommendation to a user of whether to proceed withneuromodulation therapy at the device position based on the identifiedavoidance regions.
 5. The method of claim 4 wherein providing therecommendation via the processor comprises generating a signal to theuser indicative of the avoidance regions, wherein the signal includes anaudio signal, a visual signal, a tactile signal, or a combinationthereof.
 6. The method of claim 1 wherein displaying the representationof the vessel further comprises displaying markers of target regions ofthe vessel for delivering neuromodulation therapy.
 7. The method ofclaim 1 wherein displaying the representation of the vessel furthercomprises: displaying a first portion of the vessel on therepresentation; and displaying a second portion of the vessel on therepresentation, wherein the second portion corresponds to one or moreavoidance regions of the vessel, and wherein the displayed first portionhas a lower resolution compared to the displayed second portion.
 8. Themethod of claim 1 wherein receiving the hemodynamic data comprisesreceiving data regarding blood pressure, blood flow, and/or bloodimpedance.
 9. The method of claim 1 wherein receiving the hemodynamicdata comprises receiving the hemodynamic data via a guidewire having ablood pressure sensor and/or a blood flow sensor.
 10. The method ofclaim 1 wherein receiving the hemodynamic data comprises receiving bloodpressure data via an external pressure cuff and/or receiving blood flowdata via magnetic resonance imaging (MM), a non-invasive ultrasoundDoppler shift flow meter, or a combination thereof.
 11. The method ofclaim 1 wherein receiving the digital data regarding three-dimensionalimaging of the vessel comprises receiving data acquired usingangiography, x-ray imaging, computed tomography (CT), MRI, or acombination thereof.
 12. The method of claim 1 wherein receivinghemodynamic data comprises receiving blood pressure data and/or bloodflow data measured at a position within a main portion the vessel havingat least generally laminar flow.
 13. The method of claim 1 whereinreceiving hemodynamic data comprises receiving blood pressure dataand/or blood flow data measured at a position within at least one branchvessel and/or at least one accessory vessel.
 14. The method of claim 4wherein providing the recommendation further comprises: recommendingavoiding neuromodulation therapy at one or more portions of the vesselhaving at least one hemodynamic parameter in the hemodynamic data thatexceeds a threshold hemodynamic parameter, and thereby indicates atleast one local blood flow abnormality.
 15. The method of claim 1wherein identifying avoidance regions of the vessel comprisesidentifying portions of the vessel at or proximate to an ostium, acarina, a taper region, a calcification, a fibromuscular dysplasia, ananeurysm, a bifurcation, or a combination thereof.
 16. The method ofclaim 1 wherein generating the computational fluid dynamic model of thevessel comprises applying a hemodynamic parameter derived from empiricaldata or conglomerate data.
 17. A method of optimizing neuromodulationtherapy in a blood vessel of a human patient, the method comprising:receiving, at a processor, digital data regarding three-dimensionalimaging of the vessel; receiving, at the processor, hemodynamic datarelated to the vessel; generating, at the processor, a computationalfluid dynamics (CFD) representation of the vessel based at least in parton the imaging data and the hemodynamic data, the computational fluiddynamics representation including flow parameters; identifying, via theprocessor, target regions of the vessel suitable for neuromodulationtherapy and avoidance regions of the vessel less suitable forneuromodulation therapy; and displaying, on a user interface, the CFDrepresentation of the vessel including visual indicia designating theidentified target regions and the identified avoidance regions.
 18. Themethod of claim 17, further comprising: delivering a neuromodulationcatheter to the vessel of the human patient; monitoring the location ofthe neuromodulation catheter within the vessel; and indicating, via theuser interface, the location of the neuromodulation catheter relative tothe identified target regions and the identified avoidance regions ofthe vessel.
 19. The method of claim 18, further comprising providing,via the user interface, a recommendation, made by the processor, ofwhether to proceed with neuromodulation therapy at the currentneuromodulation catheter location within the vessel, the recommendationbeing based on a comparison between the current location of theneuromodulation catheter and the identified target regions and/or theidentified avoidance regions of the vessel.
 20. The method of claim 18wherein the location of the neuromodulation catheter is monitored inreal-time.
 21. The method of claim 17 wherein receiving the hemodynamicdata related to the vessel comprises detecting at least one of bloodpressure or blood flow using a sensor disposed within the vessel. 22.The method of claim 17 wherein identifying the avoidance regionscomprises identifying portions of the vessel having low wall shearstress (WSS), high WSS, high WSS gradients, an ostium, a carina, a taperregion, a calcification, a fibromuscular dysplasia, an aneurysm, abifurcation, a region of blood flow separation, an eddy, a region ofimpinged blood flow, a region of turbulent blood flow, a region ofsecondary blood flow, or a combination thereof.
 23. The method of claim17, further comprising applying neuromodulation therapy to at least oneof the identified target regions of the vessel, wherein theneuromodulation therapy comprises energy delivery, cryotherapy, and/orchemical-based treatment.
 24. The method of claim 21 wherein the sensordisposed within the blood vessel is a sensor of the neuromodulationcatheter.
 25. A non-transitory computer readable memory storinginstructions that, when executed by a processor of a computing device,cause the computing device to perform operations for identifying atarget neuromodulation therapy region in a blood vessel, the operationscomprising: receiving data regarding three-dimensional imaging of thevessel; receiving at least one of blood pressure data or blood flow datarelated to the vessel; generating a computational fluid dynamics (CFD)model of the vessel based at least in part on the vessel imaging dataand the blood pressure and/or blood flow data; identifying targetregions of the vessel suitable for neuromodulation therapy and avoidanceregions of the vessel to avoid during neuromodulation therapy, theidentifying being based on the CFD model of the vessel; and displaying,on a user interface, a representation of the vessel including visualmarkers indicating the identified target regions and/or the identifiedavoidance regions.
 26. A system for optimizing neuromodulation therapyin a renal blood vessel of a human patient, the system comprising: aneuromodulation catheter including— an elongate shaft having a proximalportion and a distal portion, wherein the shaft is configured to locatethe distal portion intravascularly at a treatment region within thevessel of a human patient; a neuromodulation assembly at the distalportion of the shaft; and at least one sensor at the distal portion ofthe shaft, wherein the sensor is configured to transmit hemodynamic dataregarding the blood vessel; a computing device having a memory and aprocessor, wherein the memory stores instructions that, when executed bythe processor, cause the system to perform operations comprising—receiving digital data regarding three-dimensional imaging of thevessel; receiving hemodynamic data from the sensor; generating, at theprocessor, a computational fluid dynamics (CFD) model of the vesselbased at least in part on the three-dimensional imaging data and thehemodynamic data; identifying target regions of the vessel suitable forneuromodulation therapy and avoidance regions of the vessel lesssuitable for neuromodulation therapy based on the CFD model; anddisplaying a representation of the vessel including visual markersindicating the avoidance regions.
 27. The system of claim 26 wherein thesensor comprises at least one of a blood pressure sensor or a blood flowsensor.
 28. The system of claim 26 wherein the neuromodulation catheterfurther comprises a transmitter at the distal portion of the shaft,wherein the transmitter is configured to communicate, to a receiver, thecurrent location of the neuromodulation assembly in the vessel.